An Atlas of Investigation and Management
EMERGING INFECTIONS Robert A Salata, MD, FACP, FIDSA Professor of Medicine and Vice-chair Department of Medicine Chief, Division of Infectious Diseases and HIV Medicine Case Western Reserve University School of Medicine University Hospitals Case Medical Center Cleveland, Ohio, USA
David Bobak, MD, FIDSA Associate Professor of Medicine Division of Infectious Diseases and HIV Medicine Case Western Reserve University School of Medicine University Hospitals Case Medical Center Cleveland, Ohio, USA
CL INICA L P U B L IS H ING OXFORD
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Contents Preface
vii
Contributors
viii
Abbreviations
ix
1 HIV and AIDS BENIGNO RODRÍGUEZ AND ROBERT A SALATA Introduction Etiology and pathogenesis Global epidemiology Clinical manifestations Management Conclusions Further reading
1
2 Hepatitis C LUCILÉIA TEIXEIRA AND DAVID BOBAK Introduction Etiology and pathogenesis Global epidemiology Clinical manifestations Diagnosis Management Illustrative case history Conclusions Further reading 3 Emerging viral respiratory illnesses NANDHITHA NATESAN AND RANA B HEJAL Introduction SARS coronavirus Human metapneumovirus Avian influenza Conclusions References Further reading
1 1 3 5 24 28 28 31 31 31 34 38 39 41 46 47 47 49 49 51 63 68 76 77 78
vi
4 Tuberculosis C SCOTT MAHAN AND JOHN L JOHNSON Introduction Etiology and pathogenesis Global epidemiology Clinical manifestations Diagnosis Management Conclusions Further reading 5 Malaria ARLENE DENT AND CHARLES H KING Introduction Etiology and pathogenesis Global epidemiology Clinical manifestations Laboratory findings Diagnosis Management Prevention Illustrative cases Conclusions Further reading
79 79 79 81 82 92 96 98 99 101 101 101 103 104 106 106 108 110 112 115 115
6 Diarrheal disease KEITH B ARMITAGE AND DALIA EL-BEJJANI Introduction Clostridium difficile Travelers’ diarrhea Giardia Cryptosporidium Cyclospora Cholera Escherichia coli 0157:H7 Norovirus Conclusions References Further reading
117 117 119 123 123 124 126 127 128 129 129 130
Index
131
117
vii
Preface
Infectious diseases have plagued humans since the earliest times of civilization. The early history of infectious diseases was marked by unpredictable, sudden outbreaks of epidemic proportion. By the middle of the 20th century, the introduction of antibiotics and the development of effective vaccines resulted in the control and prevention of many infectious diseases, especially in industrialized countries. Despite the fact that infections remain the leading cause of death worldwide, attention to infectious diseases diminished in the 1970s and 1980s as there was a shift in focus to chronic degenerative diseases. This complacency regarding the control and prevention of infectious diseases has been associated with outbreaks of disease and the emergence of new pathogens. Emerging infectious diseases have been defined as those that newly appear in the population or have been known but are rapidly increasing in incidence or geographic distribution. New infectious diseases, frequently with unknown long-term impact, continue to be identified. Factors responsible for the emergence of infectious diseases are complex but include: ecologic changes in agriculture,
economic development, climate, human behavior and demographics, travel and commerce, technology and industry, microbial adaptation and change and erosion of public health measures. Old and new infections will occur in the future as they have in the past. Effective global surveillance efforts will be needed to blunt the emergence of such infections and to forestall epidemics and pandemics. Surveillance will need to be coupled with broad-based research efforts to devise new strategies for diagnosis, treatment, and prevention. It will also be necessary to develop new insights into microbial pathogenesis and genetics as well as host immune responses to these invading microbial pathogens. In this atlas, six emerging infectious diseases (HIV-1, hepatitis C, respiratory viruses, tuberculosis, malaria and diarrheal disease) are reviewed in terms of evolving epidemiology, microbial pathogenesis, clinical features, and important approaches to diagnosis and management. Robert A Salata, MD David Bobak, MD
viii
Contributors
Keith B Armitage, MD Professor of Medicine Division of Infectious Diseases and HIV Medicine Case Western Reserve University School of Medicine University Hospitals Case Medical Center Cleveland, Ohio, USA
Charles H King, MD, MS, FACP, FRSTMH Professor Center for Global Health and Diseases Case Western Reserve University School of Medicine University Hospitals Case Medical Center Cleveland, Ohio, USA
David Bobak, MD, FIDSA Associate Professor of Medicine Division of Infectious Diseases and HIV Medicine Case Western Reserve University School of Medicine University Hospitals Case Medical Center Cleveland, Ohio, USA
C Scott Mahan, MD Attending Physician Division of Infectious Diseases MetroHealth Medical Center Cleveland, Ohio, USA
Arlene Dent, MD, PhD Instructor Center for Global Health and Diseases Department of Pediatrics Case Western Reserve University School of Medicine University Hospitals Case Medical Center Cleveland, Ohio, USA Dalia El-Bejjani, MD Attending Physician Division of Infectious Diseases MetroHealth Medical Center Cleveland, Ohio, USA Rana B Hejal, MD Associate Professor of Medicine Division of Pulmonary and Critical Care Medicine Case Western Reserve University School of Medicine University Hospitals Case Medical Center Cleveland, Ohio, USA John L Johnson, MD Associate Professor of Medicine Case Western Reserve University School of Medicine University Hospitals Case Medical Center Cleveland, Ohio, USA
Nandhitha Natesan, MD Fellow Division of Pulmonary/Critical Care Case Western Reserve University School of Medicine University Hospitals Case Medical Center Cleveland, Ohio, USA Benigno Rodríguez, MD Assistant Professor of Medicine Case Western Reserve University School of Medicine University Hospitals Case Medical Center Cleveland, Ohio, USA Robert A Salata, MD, FACP, FIDSA Professor of Medicine Department of Medicine Chief, Division of Infectious Diseases and HIV Medicine Case Western Reserve University School of Medicine University Hospitals Case Medical Center Cleveland, Ohio, USA Luciléia Teixeira, MD, MS Clinical Associate Division of Infectious Diseases Cleveland Clinic Foundation Cleveland, Ohio, USA
ix
Abbreviations
AASLD American Association for Liver Diseases AFB acid-fast bacillus AFP alpha fetoprotein AIDS acquired immunodeficiency syndrome ALT alanine aminotransferase ARDS acute respiratory distress syndrome AST aspartate aminotransferase BCG Bacille Calmette–Guérin CDAD Clostridium difficile-associated disease CDC (US) Centers for Disease Control and Prevention CIN cervical intraepithelial neoplasia CK creatine kinase CMV cytomegalovirus CNS central nervous system COPD chronic obstructive pulmonary disease CRP C-reactive protein CSF cerebrospinal fluid CT computed tomography DNA deoxyribonucleic acid DOTS directly observed therapy, short course EBV Epstein–Barr virus EIA enzyme immunosorbent assay EKG electrocardiogram ELISA enzyme-linked immunosorbent assay ETEC enterotoxigenic Escherichia coli EVR early virologic response G6PD glucose-6-phosphate dehydrogenase GBS Guillain–Barré syndrome HAART highly active antiretroviral therapy HAI hemagglutination-inhibition HCC hepatocellular carcinoma HCV hepatitis C virus HIV human immunodeficiency virus hMPV human metapneumovirus HPV human papilloma virus HRCT high resolution chest computed tomography IBS irritable bowel syndrome
IF immunofluorescence INH isoniazid IRIS immune reconstitution inflammatory syndrome KS Kaposi’s sarcoma LCR ligase chain reaction LDH lactate dehydrogenase LTBI latent tuberculosis infection MAI Mycobacterium avium-intracellulare MDR multidrug resistant MGIT mycobacterial growth indicator tube MRI magnetic resonance imaging NHL non-Hodgkin’s lymphoma NNRTI non-nucleoside reverse transcriptase inhibitor NRTI nucleoside reverse transcriptase inhibitor OC opportunistic complications OHL oral hairy leukoplakia PCNSL primary CNS lymphoma PCP Pneumocystis jirovecii pneumonia PCR polymerase chain reaction PGL persistent generalized lymphadenopathy PI protease inhibitor PML progressive multifocal leukoencephalopathy RBM Roll Back Malaria (Program) RIBA recombinant immunoblot assay RNA ribonucleic acid RSV respiratory syncytial virus RT-PCR reverse transcriptase polymerase chain reaction SARS-CoV severe acute respiratory syndrome-associated coronavirus SIL squamous intraepithelial lesions SP sulfadoxine-pyrimethamine STD sexually transmitted disease SVR sustained virologic response TB tuberculosis TST tuberculin skin test WHO World Health Organization
Chapter 1
1
HIV and AIDS Benigno Rodríguez, MD and Robert A Salata, MD, FACP, FIDSA
Introduction The acquired immunodeficiency syndrome (AIDS) was first recognized in 1981, when a cluster of cases of uncommon opportunistic infections and malignancies was reported among otherwise healthy men who had sex with men in San Francisco, Los Angeles, and New York. Alert clinicians and immunologists recognized the unusual infections as indicative of a profound cellular immunodeficiency, a notion promptly confirmed by a diversity of laboratory assays. Alternative routes of acquisition, including parenteral, perinatal, and transfusion-associated were quickly identified, and further reports that an indistinguishable illness had been known for decades in sub-Saharan Africa began to emerge. Subsequent developments occurred at a remarkably fast pace, unprecedented for a novel infectious disease: the retrovirus now known as human immunodeficiency virus (HIV) was identified as the causative agent within 2 years of the first case reports by independent groups in France, Bethesda, and San Francisco; a serological test became available shortly thereafter; the genome was fully sequenced in 1985; and the first clinically usable therapeutic compound, zidovudine, became commercially available in 1987. Since then, combinations of drugs that act at different stages of the virus’ life cycle (see below), known as highly active antiretroviral therapy (HAART) have proven capable of suppressing viral replication to extremely low levels, and to restore, at least partially, the impaired cellular immune function that is ultimately responsible for the increased susceptibility to opportunistic infections in AIDS patients. The HIV pandemic, however, continues virtually unabated, having spread to every continent, and to all
demographic groups throughout the world. Moreover, no curative treatment is available, and predictions for the time to development of an effective, widely available, preventive vaccine are measured in decades. Thus, HIV infection and AIDS remain major health problems that concern virtually every practicing clinician, and the complexity of their management can only be expected to increase in coming years. This chapter focuses mostly on the clinically relevant aspects of HIV infection and AIDS. Excellent reviews of the biology, immunology, and virology of HIV have been published elsewhere.
Etiology and pathogenesis HIV-1 is the etiologic agent of the majority of AIDS cases worldwide. A closely related agent, HIV-2, also causes AIDS in parts of West Africa; sporadic cases occur elsewhere. Throughout the remainder of this chapter, ‘HIV’ is used to refer to HIV-1, unless otherwise indicated. HIV is a member of the lentiviridae family with a plus-stranded ribonucleic acid (RNA) genome that encodes structural, regulatory and accessory proteins, as well as the enzymatic activities; the genomic organization of HIV is shown in Fig. 1.1, and the structure of the infective viral particle is shown in Fig. 1.2. The hallmark of HIV infection is depletion of CD4+ helper T lymphocytes, with ensuing loss of immune competence. Many other immune defects are evident as HIV disease progresses, however, and not all of them can be readily accounted for by the loss of help associated with
2
HIV and AIDS
5’ LTR
gag
Integrase p7
p17
vpr vif tat vpu
pol
Protease
Reverse transcription
env
gp120
rev
nef
3’ LTR
gp41
p24
rev
tat
Fig. 1.1 The genomic organization of HIV. The complete genome is approximately 10 kb in size, and is similar to the general structure of other retroviruses. In the figure, the most relevant genes are represented in different colors, and the most important proteins they encode for are shown inside the corresponding symbols. Not all gene products are shown.
Glycoprotein 120 RNA Outer protein core Lipid membrane Inner protein core Reverse transcriptase
Fig. 1.2 Schematic view of HIV structure. CD4+ T cell destruction. Among these, defects in B cell proliferation and antibody production, impaired cytotoxic lymphocytic responses, decreased dendritic cell number and function, and profound perturbations of the cytokine milieu have all been shown, particularly in advanced stages of HIV infection. The precise mechanism by which HIV infection leads to these wide-ranging defects is incompletely understood, although they are related to HIV replication, and can be partially corrected by effective antiretroviral therapy that suppresses plasma viremia to very low levels. The vital cycle of HIV is complex and includes multiple steps that can be targeted for therapeutic purposes. These
steps are summarized in Fig. 1.3. Active HIV replication is lytic to some, but not all infected cells. Because the predominant target of HIV is the CD4+ T cell, it has been proposed that direct destruction of these cells by HIV is the predominant mechanism of immunodeficiency in progressive HIV infection. More recent evidence, however, shows that the number and distribution of infected cells, the rate of CD4+ T cell turnover and the loss of large numbers of uninfected cells through indirect, or ‘bystander’, mechanisms do not support this model as the sole explanation for HIV-related immune deficiency. Moreover, studies in HIV-infected persons receiving clinical care show that the level of HIV viremia predicts poorly the subsequent rate of CD4+ T cell loss at the individual level, further highlighting that other, indirect mechanisms in effect lead to immunodeficiency in HIV infection. Uncontrolled immune activation is an additional feature of HIV infection that may underlie the CD4+ T cell loss and other immune derangements that eventually culminate in full-blown AIDS. Similarly, advanced HIV infection is associated with depletion of thymocytes and loss of thymic function, as well as impaired bone marrow activity, all of which limit the ability to restore the accelerated CD4+ T cell losses induced by HIV. The net result is a progressively increased susceptibility to a diversity of opportunistic complications that, in the era before the introduction of HAART, were almost invariably fatal within a short period after the initial diagnosis of AIDS.
HIV and AIDS 3
Global epidemiology
HIV virion Attachment inhibitors act here
1
CD4
3 2 CCR5
Fusion inhibitors act here
CXCR4 Reverse transcriptase
Integrase
CD4+ lymphocyte
4
Nucleus
Genomic RNA
Proviral DNA
Cytoplasm
Reverse transcriptase inhibitors act here
5
Integrase inhibitors act here
Integrated proviral DNA
Viral mRNA
6
Chromosomal DNA
7
RNA polymerase
8 Genomic RNA
9
Protease inhibitors act here
Few human infections fit the description of an emerging disease better than HIV infection and AIDS. In the 25 years since its initial description, 75 million individuals worldwide have been infected with HIV, and the epidemic is now present throughout the world. The World Health Organization (WHO) estimates that, by the end of 2006, there were 39.5 million persons living with HIV/AIDS in the world, and 4.3 million acquired HIV in the previous year alone. Over 90% of these persons live in the developing world (62.5% in sub-Saharan Africa alone) and heterosexual intercourse is the route of acquisition in the vast majority of cases. Current estimates of the extent of the HIV epidemic worldwide are shown in Fig. 1.4. In addition to the sheer number of cases, the HIV epidemic has changed dramatically over the past several years, leading to a truly re-emerging epidemiological pattern worldwide. Large epidemics are expanding rapidly in eastern Europe, Asia, and India, which is now the single country with the largest number of cases worldwide. Moreover, the proportion of cases occurring in women is increasing at an alarming pace. Close to 50% of all adults living with HIV/AIDS worldwide are women, and the proportion approaches 66% in parts of sub-Saharan Africa. In the United States and western Europe, the introduction of HAART has produced dramatic reductions in HIV-related morbidity and mortality (Fig. 1.5), but trends in sex distribution are similar to those observed worldwide (Fig. 1.6). Furthermore, new cases are occurring disproportionately more often among minorities and disadvantaged populations, further changing the face of the epidemic.
Fig. 1.3 Vital cycle of HIV and sites targeted by current anti-HIV medications. After HIV binds to its primary receptor, CD4 (1), the viral envelope undergoes a conformational change that facilitates binding to another cellular coreceptor, the most important of which are the chemokine receptors CCR5 and CXCR4 (2). Interaction with the coreceptor triggers further conformational changes in the envelope that bring the viral and cellular membranes into close proximity, thereby permitting their fusion (3) through insertion of the newly exposed fusion domain of the envelope protein gp41 into the host cell membrane. The HIV nucleocapsid then enters the cytoplasm, where the RNA genomic material of the virus is reverse transcribed into DNA (4) by the virally encoded reverse transcriptase. Next, the double-stranded viral DNA enters the nucleus, where it integrates into the host genome with the aid of the HIV-encoded enzyme integrase (5). The integrated proviral DNA is then transcribed into messenger RNA (6), which serves as the template for assembly of the main viral structural proteins (7). The protein complex is cleaved by a protease into functional segments (8), thus allowing assembly and budding of the new viral particles (9) to proceed.
HIV and AIDS
Fig. 1.4 Global estimates of the HIV/AIDS epidemic at the end of 2006. (Adapted from UNAIDS and WHO, 2006 Report on the Global HIV epidemic, Geneva, UNAIDS, 2006.)
Western & Central Europe 740,000 (550,000–950,000)
North America 1.4 million (770,000–2.1 million)
North Africa & Middle East 460,000 (250,000–720,000)
Caribbean 250,000 (240,000–420,000)
Eastern Europe & Central Aisa 1.7 million (1.0–2.3 million) East Asia 750,000 (420,000–1.1 million) South & South-East Asia 7.8 million (5.1–11.7 million)
Sub-Saharan Africa 24.7 million (231.6–27.4 million)
Latin America 1.74 million (1.2–2.4 million)
Oceania 81,000 (48,000–170,000) Total 39.5 (33.4–46 million)
40 35
Percentage
Deaths per 100,000 population
4
30 25 20 15 10
100 90 80 70 60 50 40 30 20 10 0 1987
5
1989 1991
1993 1995 1997 1999
2001 2003
Male
0 1987 1989 1991 1993 1995 1997 1999 2001 2003 Unintentional injury HIV disease Cancer Heart disease Suicide Homicide Chronic liver disease Stroke Diabetes
Fig. 1.5 Trends in annual rates of death due to the nine leading causes among persons 25–44 years old, USA, 1987–2004. HIV disease was the leading cause of death among person 25–44 years old in 1994 and 1995. With the introduction of HAART in 1995, the rank of HIV disease fell to 5th place from 1997 through 2000, and to 6th place in 2001 and 2002. The spike in the death rate due to homicide in 2001 resulted from the terrorist attack on September 11. (Adapted from CDC data.)
Female
Fig. 1.6 Trends in the percentage distribution of deaths due to HIV disease by sex, USA, 1987–2004. The proportion of females among persons who died of HIV disease increased from 10% to 26% during this period, highlighting the increasing burden of disease among females in the US, as is the case in other countries. Because heterosexual transmission is emerging as the predominant mode of transmission, this trend can be expected to grow in the coming years. (Adapted from CDC data.)
HIV and AIDS 5
Clinical manifestations The clinical manifestations of HIV infection and AIDS are diverse and can affect virtually any organ system. The time to development of specific symptoms or syndromes varies considerably from person to person, and many cases remain asymptomatic for very prolonged periods. Nevertheless, HIV-related immunodeficiency develops in most cases as a predictable sequence of events, in which the massive depletion of CD4+ T cells that characterizes AIDS occurs only after a clinically silent interval. During this period, few clinical indications of HIV infection exist, despite vigorous viral replication in the lymphoid tissues and ongoing plasma viremia. This sequence of events is summarized in Fig. 1.7. The first clinical manifestation of HIV infection may be a mononucleosis-like syndrome, termed acute retroviral syndrome, which occurs in over 50% of cases within 2–6 weeks of initial infection. Symptoms are nonspecific and may include fever, sore throat, lymph node enlargement, arthralgias, and headache and usually persist for several days to 3 weeks; in a significant proportion of symptomatic cases, the manifestations are severe enough to warrant medical attention. A maculopapular rash is common, as is
nonspecific lymphadenopathy (Fig. 1.8), and some patients may present with self-limited aseptic meningitis, which manifests as cerebrospinal fluid (CSF) pleocytosis and isolation of HIV from CSF. In some cases, the acute retroviral syndrome may be accompanied by thrush or even opportunistic infections during the transient CD4+ T cell decline seen early in the disease course. Table 1.1 summarizes the most common clinical manifestations of acute retroviral syndrome. From the laboratory standpoint, the acute retroviral syndrome can be diagnosed on the basis of a negative HIV enzyme-linked immunosorbent assay (ELISA) and a positive antigen-based or HIV RNA test in a patient with risk factors. After the acute retroviral syndrome, the majority of subsequent clinical manifestations are due to complications emerging from progressive immunodeficiency. These infections will be discussed according to the stage at which they characteristically present. It should be kept in mind, however, that while diseases that are typical of profound immunodeficiency rarely appear at earlier stages, those that occur with high CD4+ T cell counts can obviously also
CD4+ T lymphocyte count (cells/mm3)
HIV RNA copies/ml plasma
Culturable plasma viremia (dilution titer)
Fig. 1.7 Natural history of Primary infection 1200 107 Opportunistic untreated HIV disease. Shortly Death ± Acute HIV syndrome disease 1100 after infection, viremia reaches Wide dissemination of virus 1000 Seeding of lymphoid organs extremely high levels, while CD4+ 106 1/512 900 count decreases to levels that Clinical latency 1/256 800 may be sufficient for the 105 1/128 700 Constitutional development of certain 1/64 symptoms 600 opportunistic complications. 1/32 500 104 During this period, patients may 1/16 400 experience the manifestations of 1/8 300 the acute retroviral syndrome, and 103 1/4 200 are highly infectious, thus making 1/2 100 a high index of suspicion of 102 0 0 paramount importance. After this 0 3 6 9 12 1 2 3 4 5 6 7 8 9 10 11 initial phase, viremia decreases to Weeks Years a level (referred to as ‘set point’) at which it will remain, relatively constant, during the subsequent phase. At the same time, CD4+ T cell count rebounds, but does not return to pre-infection levels. A relatively asymptomatic period follows, during which there is ongoing viral replication and a slow but demonstrable decline in CD4+ T cell count. This phase ends years after infection with a precipitous fall in CD4+ T cell count and an exponential rise in plasma HIV RNA level, which heralds the beginning of AIDS. (Adapted from Fauci AS, Pantaleo G, Stanley S, et al. Immunopathic mechanisms of HIV infection. Ann Intern Med 1996;124:654.)
6
HIV and AIDS
Complications occurring with CD4+ T cell counts >500/mm3
Table 1.1 Clinical manifestations of acute retroviral syndrome Sign or symptom Fever Lymphadenopathy Pharyngitis Rash Myalgia/arthralgia Diarrhea Headache Nausea/vomiting Hepatosplenomegaly Thrush Neurologic symptoms
% 96 74 70 70 54 32 32 27 14 12 12
(Data from Kahn JO, Walker BD. Human immunodeficiency Virus Type 1 infection. N Engl J Med 1998;339:33.)
occur at later stages. A useful classification that includes both clinical and laboratory markers is the US Centers for Disease Control (CDC) staging system, shown in Table 1.2.
Persistent generalized lymphadenopathy (PGL) can begin with the acute retroviral syndrome (Fig. 1.8), and is defined as two or more extrainguinal regions with lymphadenopathy persisting for at least 3–6 months in the absence of an alternative explanation. Up to 50–70% of HIV-infected patients may develop PGL, but PGL is not associated with adverse consequences in those individuals. Excluding a treatable etiology is critical, particularly with more localized lymphadenopathy. Some patients will experience constitutional symptoms (low-grade fevers, fatigue, and night sweats), diarrhea, or unexplained weight loss during the early stages of HIV infection; again, excluding other etiologies is imperative. Oral and vaginal candidiasis (Fig. 1.9) can also appear at all stages of HIV disease, although they increase in frequency as the CD4+ T cell count falls below 500 cells/mm3. Thrush presents as adherent, nonpainful, off-white exudates that can be scraped off with a tongue depressor, leaving a denuded area of mucosa. Dermatomal herpes zoster (Fig. 1.10) is another frequent early manifestation; in more advanced stages, the presentation may involve multiple dermatomes, prolonged persistence of lesions, or systemic dissemination.
Table 1.2 US Centers for Disease Control 1993 revised classification system for HIV infection in adults and adolescents CD4+ T cell category
Category 1: ≥500 cells/mm3 Category 2: 200–499 cells/mm3 Category 3: 10 years Alcohol ingestion Coinfection with HIV Human leukocyte antigen type B54 Viral genotype 1b
Table 2.7 Signs of advancing fibrosis in hepatitis C
• • • • •
Elevated prothrombin time Thrombocytopenia Hypoalbuminemia Reversed albumin to globulin ratio Aspartate aminotransferase (AST) level > alanine aminotransferase (ALT) level
advancing fibrosis in the patient with chronic hepatitis C (Table 2.7). In addition, persons who have chronic liver disease are at increased risk for fulminant hepatitis A. Chronic HCV infection can be associated with a wide variety of extrahepatic manifestations ranging from skin disorders such as porphyria cutanea tarda and lichen planus to serious lymphoproliferative disorders such as B cell lymphoma. The nature of this association is unclear for many extrahepatic syndromes. Because HCV is able to replicate in certain types of lymphoid cells, however, it is often speculated that HCV-mediated dysregulation of the host immune system may play a role in the development of some of these conditions. Laboratory evidence of cryoglobulinemia, for example, can be found in up to 50% of patients, although only 10–15% of these patients have specific signs or symptoms of this disorder (weakness, arthralgias, and purpura). HCV-infected patients often complain of arthralgias and the occasional patient will develop true polyarthritis. Again, there is a suggestion that
Hepatitis C 39
Female sex, young age at infection Slow
Rate of progression
≥30 years
Normal liver
Acute infection
Chronic infection develops in ~85%
Chronic hepatitis
Cirrhosis develops in 20%
Risk of carcinoma, 1–4% per year
Alcohol use, coinfection Fast
≤20 years
Fig. 2.12 Disease progression rates following acute hepatitis C infection.
the underlying pathophysiology is, at least in part, related to some aspect of the HCV infection itself. Similarly, certain forms of chronic renal disease, such as membranoproliferative glomerulonephritis, appear to be associated with chronic hepatitis C. In certain instances, eradication of viremia by HCV therapy may show a beneficial effect on the severity of some of these extrahepatic syndromes.
Diagnosis HCV infection is most commonly diagnosed by a screening test for antibody to HCV using a specific enzyme immunosorbent assay (EIA) designed to detect certain HCV proteins (Fig. 2.13). The second generation of this test, the EIA-2, is the most commonly used serologic test in the United States. This assay detects antibodies directed to recombinant antigens derived from the core and nonstructural proteins 3 (NS3) and 4 (NS4) of the HCV. EIA2 identifies at least 95% of chronically infected patients, but detects only 50–70% of acute infections. Because HCV EIA tests have been optimized for sensitivity (i.e. for screening), a positive or indeterminate EIA-2 test is usually followed by
performance of a confirmatory assay. The most commonly used confirmatory test is another serologic assay known as the recombinant immunoblot assay-version two (RIBA-2). The RIBA-2 measures immunoreactivity against specific antigenic bands representing HCV polypeptides. RIBA-2 is most often helpful in evaluating positive or indeterminate results obtained with the EIA-2 in low-risk populations. The third generation of the HCV EIA, the EIA-3, has been approved for screening blood products in the United States and has started to be used for diagnosis as well. The EIA-3 detects an additional antigen derived from the non-structural region (NS5). This test can detect antibody against HCV as early as 6 weeks following infection. The overall sensitivity of the EIA-3 is estimated to be greater than 97% and appears likely to decrease the incidence of indeterminate results observed in certain screening scenarios. No medical agency currently advocates routine screening for HCV infection in the general population. Certain organizations have identified several characteristics believed to place individuals at increased risk for hepatitis C and recommend such individuals be screened for HCV infection (Table 2.8). A positive serological test for HCV cannot distinguish
40
Hepatitis C
Negative
Screening test for anti-HCV
STOP
Positive OR
RIBA for anti-HCV
Negative
STOP
Nucleic amplification test for HCV RNA
Indeterminate
Positive
Additional laboratory evaluation (e.g. PCR, ALT) Negative PCR Normal ALT
Positive
Medical evaluation
Positive PCR Abnormal ALT
Fig. 2.13 Flow chart for diagnostic testing of hepatitis C infection.
Table 2.8 Indications for hepatitis C virus testing1
Routine testing recommended: • Ever injected illegal drugs • Received blood products and/or organ transplantation before July 1992 • Received clotting factors manufactured before 1987 • Ever received chronic hemodialysis • Laboratory evidence of liver disease • Current or long-term sexual partners of a hepatitis C-infected person2 • Child born to a hepatitis C-infected mother • Received a needle stick or high-risk mucosal exposure to hepatitis C-infected blood 1Adapted
Uncertain risk, consider individualized testing3: • Casual or short-term sexual partner of a hepatitis C-infected person • History of multiple sexually transmitted diseases • Ever used non-injection illegal drugs • Ever received a body piercing or tattoo • Received a tissue transplant • Received acupuncture or religious scarification while residing in highly endemic area
from the recommendations of the United States Centers for Disease Control and Prevention (CDC) and the American Association for the Study of Liver Diseases (AASLD) 2Recommended only by AASLD 3Not recommended routinely by CDC or AASLD
Hepatitis C 41
past from current infection. In order to determine if the patient has active HCV infection, a molecular assay designed to measure the presence of HCV RNA should be performed. Qualitative and quantitative HCV RNA assays are commercially available and tests are based on nucleic acid signal amplification (bDNA) or the polymerase chain reaction (PCR). In most instances, PCR-based assays have become the favored technique due to their generally higher sensitivities. Differences in the currently available HCV PCR tests are based primarily in the lower limit of detection achievable, and the usable overall range of results that are obtainable. In general, qualitative tests are slightly more sensitive and are the primary confirmatory test used in most countries. Quantitative HCV RNA tests are also very helpful and are used to assess the level of viremia present in an infected individual. These quantitative determinations have some value in assessing the level of disease activity (e.g. if very low or very high), but are most useful in following a patient’s response to therapy and for the detection of relapse following completion of therapy (see below). HCV genotype testing is recommended for all HCVinfected individuals because the likelihood of response to standard HCV therapy varies widely based on genotype (see below). Although liver biopsy is not required to make the diagnosis of hepatitis C, this technique remains the only definitive way to assess the stage of liver inflammation and fibrosis and is helpful in predicting the possible rate of disease progression (Fig. 2.5). Although the value of routine liver biopsy for all patients with hepatitis C continues to be debated, for a number of patients biopsy results provide very useful information. A number of serum markers are being evaluated in an effort to develop a non-invasive way of determining the stage of liver inflammation and fibrosis, but no assays are yet fully accepted as an adequate substitute for the information that can be provided by a liver biopsy in selected patients.
Management Current treatment regimens for hepatitis C produce sustained virologic responses in a subset of patients with hepatitis C. For this reason, every HCV-infected patient should be evaluated for suitability of possible antiviral treatment. Even those patients deemed not eligible for antiviral treatment can, and should, make lifestyle changes that can favorably impact on the progression of their disease.
Paramount among these interventions is limiting or eliminating the ingestion of alcohol, a known cofactor for progression of HCV infection. In addition, administration of potentially hepatotoxic medications should be avoided when possible. Most experts believe that a low dose of acetaminophen (e.g. not more than 2 g over 24 hours) is safe for those HCV-infected patients with normal hepatic function. Because HCV-infected individuals are at risk of contracting a more severe form of acute hepatitis A or B, immunization against these diseases should be provided to susceptible patients. Screening HCV-infected patients for HCC is commonly recommended, although the efficacy of this practice for patients without cirrhosis is not well established. Serum alpha fetoprotein (AFP) levels and abdominal ultrasound examinations are the most commonly performed screening techniques. AFP levels are not specific for HCC and are frequently modestly elevated due to the effects of HCV infection itself. Ultrasound examinations are sensitive enough to detect even small hepatic lesions, but the frequency with which the test should be performed has not been established. It should be noted that some patients with hepatitis C, especially those with cirrhosis, appear to still be at risk for the development of HCC even after successful completion of antiviral therapy. Work continues into developing more sensitive and specific serum markers for the detection of HCC at an early stage. As noted above, all patients with chronic hepatitis C should be evaluated for possible antiviral treatment regimens. Many factors influence the decision to treat any specific patient and include age, genotype, assessment of disease activity, and the presence of comorbid medical, psychological, or substance abuse issues. In general, adults younger than 70 years old with evidence of active inflammation on liver biopsy or elevated ALT are considered to be potential candidates for treatment. Indications for treatment of patients with very mild disease on liver biopsy or normal ALT levels are less clear-cut, although there has been increased support for treatment in these types of patient as well. Patients with compensated cirrhosis can be evaluated for treatment, but those individuals with advanced cirrhosis secondary to hepatitis C should generally be referred for evaluation for possible liver transplantation. Hepatitis C is the leading indication for liver transplantation in most countries where transplantations are performed. All currently available treatment regimens for hepatitis C
42
Hepatitis C
Table 2.9 Forms of interferon currently available for treatment of hepatitis C
Table 2.10 Improvements to interferon-α by pegylation
• • • • •
• • • • • •
Interferon-α-2a Interferon-α-2b Pegylated-interferon-α-2a Pegylated-interferon-α-2b Consensus interferon
are based on the use of various injectable forms of recombinant human interferon-α (Table 2.9). The exact mechanism of action of the interferons in the treatment of HCV infection is incompletely understood, but most evidence indicates that interferon-α can directly enhance immune-mediated activity against HCV and augment cellular mechanisms that interfere with the intracellular replication cycle of HCV as well. Recombinant forms of interferon-α-2a, interferon-α-2b, and consensus interferon are approved for use in the United States and many other countries for the treatment of hepatitis C. Pegylated forms of interferon-α-2a and -α-2b are available and allow for weekly dosing because of their prolonged half-life. Several large studies have shown that the pegylated forms produce superior response rates when compared with their related non-pegylated formulations (Table 2.10). For almost all patients, interferon is combined with an orally administered analog of guanosine known as ribavirin. This combination therapy markedly increases the rate of sustained virologic response (SVR) as compared with interferon-α monotherapy (Table 2.11). SVR is commonly defined as negative molecular assays for HCV RNA 6 months to 1 year following completion of therapy. Relapse of HCV infection following SVR is extremely rare. The duration of the treatment regimen as well as the predicted likelihood of response for patients with hepatitis C varies dramatically depending on their particular HCV genotype (Fig. 2.14). For example, patients with genotype 1 infections are generally treated for a total duration of 48 weeks and have an expected rate of SVR of 30–40%. In contrast, patients with genotype 2 or 3 infections have an expected rate of SVR of 80–90% and are usually treated for only 24 weeks (i.e. twice the achievable rate of SVR when treated for only half the time of genotype 1 patients). As
Improved absorption Optimized distribution Decreased rate of clearance Reduced proteolysis Decreased immunogenicity Improved efficacy
Table 2.11 Overall hepatitis C SVR rates for interferon (INF)-based treatments
INF-α (24 wks) IFN-α (48 wks) IFN-α/ribavirin (24 wks) IFN-α/ribavirin (48 wks) Peg-IFN-α/ribavirin (48 wks)
6% 16% 33% 41% 54%
Average overall sustained virologic response (SVR) rate pooled from published studies and registration trials
noted above, a large number of factors must be taken into consideration in order to decide whether treatment should be recommended for any particular patient. It is important to estimate both the level of disease activity and likelihood of treatment-related toxicities when formulating a treatment plan. Examples of relative or absolute contraindications to interferon/ribavirin therapy are varied and include decompensated cirrhosis, pregnancy, serious cardiac disease, significant renal disease, certain autoimmune diseases, active intravenous drug use, major psychiatric disorders, pre-existing cytopenias, and renal transplantation (Tables 2.12, 2.13). Those patients who undergo combination therapy receive a quantitative HCV assay 12 weeks after the initiation of treatment (Fig. 2.14). An individual whose HCV viral load has become non-detectable or which has decreased by at least two logs compared with pre-treatment values is considered to have achieved an early virologic response
Hepatitis C 43
PEG IFN/ribavirin treatment Baseline genotype and quantitative HCV RNA
Week 12
Re-test quantitative HCV RNA
HCV RNA decreased 2 log vs. baseline
HCV RNA undetectable
HCV RNA not decreased 2 log vs. baseline
HCV RNA detectable
STOP
Repeat HCV RNA at 12 weeks
Complete treatment: A: genotype 1 (36 more weeks) B: genotypes 2 or 3 (12 or more weeks)
Negative
Positive
STOP
Fig. 2.14 Treatment decision timepoints for hepatitis C.
(EVR). EVR is highly predictive of developing a subsequent SVR (Fig. 2.14) and such patients are continued on therapy until the stop date is reached. Patients who do not achieve an EVR are usually withdrawn from therapy because several large studies have shown that their likelihood of achieving an SVR is minimal. Patients who remain HCV PCR negative 6–12 months after the completion of therapy are considered to have achieved SVR. A proportion of patients who achieve EVR will stop therapy due to significant treatment-related toxicities (Tables 2.14, 2.15). Again, adverse effects of interferon/ribavirin combination therapy are numerous and include myalgias,
fatigue, anemia and other cytopenias, thyroid disease, exacerbation of underlying autoimmune disease, rash, and psychiatric disorders (especially major depression). Many of these adverse effects can be managed sufficiently to allow continuation of therapy. Anemia is a particularly common and bothersome problem because it can be caused by both interferon and ribavirin. Early recognition of anemia and institution of erythropoietin treatment permit many patients to complete therapy without significantly reducing doses of interferon or ribavirin. This effect is important because recent evidence suggests that achieving adequate levels of ribavirin are imperative to optimize a patient’s chance of
44
Hepatitis C
Table 2.12 Contraindications for interferon-α treatment
Absolute: • Decompensated cirrhosis • Symptomatic cardiovascular disease • Severe anemia, neutropenia, or thrombocytopenia • Seizure disorder (active) • Solid organ transplant (except liver) • Current or previous psychosis • Severe depression Relative: • Active autoimmune disease • Thyroid disorders • Poorly controlled diabetes mellitus • Active substance use (alcohol or intravenous drug) (Adapted from Lauer GM, Walker BD. Medical progress: hepatitis C infection. N Engl J Med 2001; 345:41–52.)
Table 2.13 Contraindications for ribavirin treatment
Absolute: • Pregnancy • Inability or unwillingness to use reliable contraception • Severe or end-stage renal disease • Significant anemia • Symptomatic cardiovascular disease
Table 2.14 Side-effects of interferon-α treatment
Incidence >30%: • Fever • Chills/rigors • Myalgia • Arthralgia • Headache • Fatigue • Thrombocytopenia • Autoantibody formation Incidence 1–30%: • Malaise • Anorexia • Nausea • Diarrhea • Retinopathy • Activation of autoimmune disease • Taste alteration • Rash • Irritability • Insomnia • Emotional lability • Depression • Cognitive disorders • Decreased libido • Anemia • Leukopenia
Relative: • Poorly controlled hypertension • Elderly
Incidence 30%: • Nausea • Hemolysis Incidence 1–30%: • Pruritus • Sinus congestion • Rash • Anemia Incidence 60 years
Emerging viral respiratory illnesses 55
Recovery (89%)
Exposure to SARS
‘Flu-like’ illness
Non-productive cough, shortness of breath
Incubation period
Prodrome
Lower respiratory phase
~2–10 days Up to 13 days reported
Few days
From day 4 onwards
Outcome
Death (11%)
Fig. 3.6 The clinical phases of SARS.
phase (Fig. 3.6). The incubation period varies between 2 and 10 days. Unlike many of the common viral respiratory pathogens, evidence suggests that there are rather few asymptomatic or mild illnesses associated with SARS-CoV, except for children, in whom the disease is uncommon, generally mild, and self limited. Typical adult illness begins with a prodrome of non-specific symptoms including highgrade fever, chills/rigors, myalgias, headache, and diarrhea (Fig. 3.7). Upper respiratory tract symptoms are less common. The clinical course tends to be insidious, and patients frequently improve transiently prior to developing lower respiratory symptoms in the second week of illness, with non-productive cough, dyspnea, and hypoxia. In 10–20% of hospitalized patients, symptoms progress to respiratory failure requiring intubation and mechanical ventilation. It is unclear whether this clinical deterioration is due to ongoing viral replication or uncontrolled immune response mediated by host defenses. Lymphocytopenia at presentation is common. Patients often go on to develop leukopenia and thrombocytopenia with the onset of respiratory symptoms. Elevated aminotransferases, creatinine kinase, and lactate dehydrogenase are also reported (Fig. 3.8). Moreover, these variables tend to worsen at different time points over the disease course (Fig. 3.9).
Fever Chills/rigors headache Myalgia Malaise Rhinorrhea Sore throat Cough Dyspnea Pleurisy Anorexia Nausea/vomiting Diarrhea 0
20
40 60 Percentage
80
100
Fig. 3.7 SARS clinical symptoms at presentation. (Data from almost 2000 patients are compiled from several series, including Avendano M, et al., 2003; Booth CM, et al., 2003; Chan PK, et al., 2003; Donnelly CA, et al., 2003; Hsu LY, et al., 2003; Lee N, et al., 2003; Peiris JS, et al., (B), 2003; Poutanen SM, et al., 2003; Rainer TH, et al., 2003; Tsang KW, et al., 2003; Zhong NS, et al., 2003.)
56
Emerging viral respiratory illnesses
Anemia
10.3
Defervescence Initiation of steroid Worst CXR findings ALT LDH AST CRP CK Leukopenia Lymphocytopenia Thrombocytopenia
Leukopenia Lymphocytopenia Thrombocytopenia Increased ALT Increased LDH 0
20
40 60 Percentage
80
8 9.6 13.3 10.8 10.3 8.5 7.8 7.5 7.0 6.9
0
100
5 10 15 Days after disease onset
20
Fig. 3.8 Initial laboratory abnormalities in patients with SARS. (Data from close to 500 patients are compiled from several series, including Booth CM, et al., 2003; Hsu LY, et al., 2003; Lee N, et al., 2003; Peiris JS, et al. (B), 2003; Poutanen SM, et al., 2003; Tsang KW, et al., 2003; Zhao, Z, et al., 2003.) (LDH: serum lactate dehydrogenase level; ALT: serum alanine aminotransferase.)
Fig. 3.9 The time relationships between the time points of defervescence, initiation of steroid, and when chest radiographic finding, as well as various laboratory parameters became most severe. Mean and standard deviation (days) are presented. (CXR: chest radiography; ALT: alanine aminotransferase; LDH: lactate dehydrogenase; AST: aspartate aminotransferase; CRP: C-reactive protein; CK: creatine kinase.) (Adapted from CDC data.)
Chest radiographs in SARS are usually abnormal (Table 3.5). Approximately 50% of patients present with unilateral focal consolidation. Lower lobe predominance is rather common. While patients presenting early can have a normal film initially, they uniformly develop some abnormality by
the seventh day of their illness. In the setting of high clinical suspicion and normal chest X-ray, high resolution chest computed tomography (HRCT) may identify early parenchymal abnormalities and should be considered. Illustrative cases are shown in Figs. 3.10–3.12.
Table 3.5 Radiographic features of severe acute respiratory syndrome
Chest radiograph • Normal, only early in course • Peripheral alveolar infiltrates (most common): – Basilar predilection – Often multifocal – Nodular infiltrate (early) • Non-cardiogenic pulmonary edema • Pleural effusion rarely • Pneumomediastinum • Absence of: – Adenopathy – Cavitation
High resolution computed tomography • Ill-defined ground-glass opacification • Reticulation • Irregular interlobular septal thickening • Subpleural reticulation • Late manifestations (patients surviving respiratory failure): – Bronchiectasis – Honey-combing and fibrosis
Emerging viral respiratory illnesses 57
A
B
Fig. 3.10 A 55-year-old healthy man with history of recent travel to Hong Kong presents with fever, dyspnea, and cough. A: Initial chest radiograph with extensive bilateral reticulo-nodular infiltrates. B: Chest radiograph 12 hours later with marked progression to acute respiratory distress syndrome. (From Nicolaou S, et al., 2003.)
A
B
C
Fig. 3.11 A 48-year-old male who presented with myalgias, headache, dry cough, leukopenia, and fever of 38°C. A: Initial chest radiograph demonstrates focal areas of consolidation in the left lower lobe and right suprahilar area. B: Chest radiograph obtained 5 days after admission reveals progression of consolidation and decreased lung volumes. C: Chest radiograph obtained 9 days after admission shows marked clearing with associated clinical improvement. (Copyright 2003, contributed by Yeun-Chung Chang, MD, Taipei, Taiwan, all rights reserved. From Armed Forces Institute of Pathology website.)
58
Emerging viral respiratory illnesses
A
C
B
Fig. 3.12 High-resolution computed tomography scan findings in patients with SARS. A: Involvement in multiple segments. Lesions are of various sizes, and are distributed in a peripheral manner. B: Ground-glass opacification. Underlying vascular architecture (arrow) is clearly visible. The bronchi are dilated. C: Mixed ground-glass opacification and consolidation. Air bronchogram (arrow) is present in the center of the consolidation. D: Ground-glass opacification and thickened interlobular septa (arrow) and intralobular interstitium (crazy-paving pattern). (From Wong KT, et al., 2003.)
D
Pathology There are no specific histologic features for this disease. The principal pathologic process is that of diffuse alveolar damage at its various stages. Bronchiolar fibrin deposition, pneumocyte cytomegaly, atypia, and multinucleated giant cells are commonly observed (Fig. 3.13). Later, during the organizing phase, fibroblast proliferation tends to occur in the interstitium and alveolar spaces. Although inclusion bodies are not seen commonly, electron microscopy can detect viral particles consistent with coronavirus in infected cells (Fig. 3.14).
Laboratory diagnosis The isolation of this organism by culture is most successful on Vero-E6 cells or fetal rhesus monkey kidney cells (Fig. 3.15). However, this process is complex and not widely available. Moreover, early isolation of the SARS-CoV is tricky due to the initial low viral load in the respiratory epithelium. Thus, other methods are implemented to confirm the diagnosis (Table 3.6).
Table 3.6 Diagnostic tests for severe acute respiratory syndrome-associated coronavirus and their corresponding diagnostic yield over time Test
Diagnostic yield (%) Reverse transcriptase polymerase chain reaction Nasopharyngeal aspirate 80 in first 3 days 68 day 14 Stool
97 day 14
Urine
42 day 15
Serum (quantitative SARS-CoV RNA)
80 day 1 75 day 7 45 day 14
Serology Immunoglobulin G to SARS-CoV
15 day 15 60 day 21 >90 day 28
Emerging viral respiratory illnesses 59
A
B
C
D
Fig. 3.13 Pathologic findings in SARS. A: Homogeneous-appearing hyaline membranes (arrow) edematous alveolar walls (H&E stain, x200). B: Organizing diffuse alveolar damage is characterized by loose fibroblastic proliferation in alveolar spaces (arrow) and within the interstitium (arrowhead) and type II pneumocyte hyperplasia (H&E stain, x100). C: Acute bronchopneumonia is characterized by polymorphonuclear leukocytes filling alveolar spaces, in this case associated with alveolar hemorrhage (H&E stain, x200). D: Cytologically atypical epithelial cells are present within alveolar spaces (H&E, x400). (Courtesy of Armed Forces Institute of Pathology.)
Fig. 3.14 Coronavirus-infected cell in broncho-alveolar lavage. (Courtesy of CDC.)
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Emerging viral respiratory illnesses
Reverse transcriptase polymerase chain reaction (RTPCR) is the preferred method for laboratory confirmation of SARS. Optimal specimen for viral detection depends on the phase of the illness (Table 3.7) and site of care (Fig. 3.16).
Fig. 3.15 This thin section electron micrograph of an infected Vero-E6 cell reveals particles of coronavirus. Note the coronaviruses contained within cytoplasmic membrane-bound vacuoles, and cisternae of the rough endoplasmic reticulum. (Courtesy of CDC.)
Table 3.7 Specimens for severe acute respiratory syndrome-associated coronavirus testing: priority specimens and timing for collection Specimen by test type
3 weeks after symptom onset
+3
++
+
Bronchoalveolar lavage, tracheal aspirate, or pleural fluid tap4
+
++
+
Nasopharyngeal wash/aspirate
+
++
+
Nasopharyngeal and oropharyngeal swabs
+
++
+
Serum (serum separator tube)
++
+
Not recommended
Blood (plasma) (EDTA/purple top tube for plasma)
++
+
Not recommended
++
++
++
RT-PCR1 for viral RNA Sputum2
EIA1 for antibody detection Serum5 (serum separator tube)
The likelihood of detecting infection is increased if multiple specimens, e.g. stool, serum, and respiratory tract specimens are collected during the course of illness 1Because
of the investigational nature of both the SARS RT-PCR (reverse transcriptase-polymerase chain reaction) and the SARS EIA (enzyme immunoassay), it is recommended that the clinician obtain a signed informed consent form from the patient. In the US the consent forms for these tests can be found at: www.cdc.gov/ncidod/sars/lab/rtpcr/consent.htm. and www.cdc.gov/ncidod/sars/lab/eia/consent.htm
2A
sputum specimen is preferred if the patient has a productive cough
3The
more checks, the better the results from a particular specimen at a specific point in the illness
4Consider 5Also
these specimen types if sputum is not available
collect a convalescent specimen >28 days post-onset
Emerging viral respiratory illnesses 61
can be done as well, with enzyme immunoassay as the preferred technique. However, the mean time to seroconversion is close to 20 days, making serologic testing of limited value in early diagnosis confirmation.
Nasopharyngeal aspirates or nose or throat swabs are best in the first few days, whereas lower respiratory secretions, stool, and urine have a higher yield towards the second week of the illness. Serologic testing for antibodies to SARS-CoV
Recommended specimens for evaluation of potential cases of SARS
Outpatient
Inpatient
Fatal
Upper respiratory tract Nasopharyngeal wash/aspirate Nasopharyngeal and oropharyngeal swabs
Upper respiratory tract Nasopharyngeal wash/aspirate Nasopharyngeal and oropharyngeal swabs
Lower respiratory tract Sputum
Lower respiratory tract Broncheoalveolar lavage, tracheal aspirate, or pleural fluid tap Sputum
Tissue Fixed tissue from all major organs (e.g. lung, heart, spleen, liver, brain, kidney, adrenals) Frozen tissue from lung and upper airways (e.g. trachea, bronchus)
Blood Serum – acute and convalescent (>28 days postonset) Blood (plasma) Stool
Blood Serum – acute and convalescent (>28 days post-onset) Blood (plasma) Stool
Upper respiratory tract Nasopharyngeal wash/aspirate Nasopharyngeal and oropharyngeal swabs Lower respiratory tract Broncheoalveolar lavage, tracheal aspirate, or pleural fluid tap Blood Serum Blood (plasma) Stool
Fig. 3.16 Recommended specimen collection for SARS laboratory testing. (Adapted from CDC data.)
62
Emerging viral respiratory illnesses
Treatment
Outcomes
Although many modalities of treatment were used during the SARS outbreak, no definite evidence points towards any specific therapy. Antiviral agents, ribavirin and, less frequently, protease inhibitor combination lopinavir/ritonavir were used empirically to treat patients with SARS. Ribavirin, unable to inhibit SARS-CoV in vitro, was cited as beneficial in several case reports but not in a conducted controlled trial. Its use was typically confounded by the addition of other agents mainly steroids, and a multitude of adverse reactions including hemolytic anemia, hypocalcemia, and hypomagnesemia. On the other hand, the lopinavir/ritonavir combination, used towards the end of the outbreak, was shown to have in vitro activity against the SARS-CoV and, when used early, improved outcomes. Steroids were the mainstay of therapy during the SARS outbreak. While some studies associated steroid use with improved outcomes, others did not. Additional agents, investigated late in the outbreak, have been successful in vitro, and may be of value in a future SARS outbreak. These include viral binding inhibitors, fusion inhibitors, glycyrrhizin, non-steroidal immunemodulators like interferon, and nitric oxide.
Retrospective studies of SARS survivors revealed that many complain of physical limitation due to generalized weakness and/or shortness of breath in the months following hospital discharge. In this population, 15–25% of confirmed SARS cases had pulmonary diffusion abnormalities and associated fibrosis in follow-up testing. Fibrotic lung changes were most common in patients with severe illness. Significant improvement of pulmonary function over time was noted, suggesting that the mechanism of lung injury in SARS may be different from that seen with other pulmonary diseases.
Prevention Prevention of SARS is centered upon controlling the possible routes of re-emergence of the SARS-CoV. These routes include persistent shedding from previously infected human hosts, spread from animal reservoirs, and accidental laboratory exposures. Several isolated incidents of laboratory-acquired SARS have been reported, highlighting the importance of adherence to biosafety guidelines (Table 3.8).
Table 3.8 Summary of CDC recommendations for expanded precautions Category Contact precautions
Elements • Single patient room (preferred) • Gloves for all contact with patient and environment of care • Isolation gown for all patient contact
Droplet precautions
• Single patient room (preferred) • Surgical mask within 3 feet (1 m) of patient • Eye protection within 3 feet (1 m) of patient
Airborne infection isolation
• Private room with monitored negative air pressure relative to surrounding areas and 6–12 air exchanges per hour • Appropriate discharge of the air to the outdoors or monitored high-efficiency filtration of room air before recirculation • Doors closed except as needed for entry and exit • National Institute for Occupational Safety and Health (NIOSH) approved respiratory protection (e.g. N-95 respirator) for entry to rooms of patients with infectious pulmonary or laryngeal M. tuberculosis, draining skin lesions with M. tuberculosis, SARS-CoV disease, smallpox, and viral hemorrhagic fevers
Emerging viral respiratory illnesses 63
In order to prevent possible future outbreaks of SARS, ongoing surveillance is necessary in high-risk areas. Even in low-risk areas, the US Centers for Disease Control and Prevention (CDC) has recommended consideration of the diagnosis of SARS in patients requiring hospitalization for radiologically confirmed pneumonia or acute respiratory distress syndrome (ARDS) in the absence of person–person transmission of SARS, only if the patient has one of the following risk factors in the 10 days prior to onset of symptoms:
Human metapneumovirus Background Human metapneumovirus (hMPV) was first isolated by van den Hoogen in 2001. Initially described in a group of 28 epidemiologically unrelated children in the Netherlands, this new member of the paramyxovirus family has since been recognized as an important pathogen of acute respiratory tract infections in all age groups, worldwide.
Virology • Travel to high-risk areas (China, Hong Kong, or Taiwan) or close contact with a symptomatic person with recent travel to these areas. • Employment in a high-risk occupation (i.e. health care worker or laboratory worker in contact with live virus). • Patient is a part of a cluster of unexplained cases of atypical pneumonia. Additionally, SARS-CoV vaccines are in progress of development. Current trials are focusing on conventional, inactivated formulations which have proven safe and effective in animals. Others, on the other hand, are using virus vector recombinants expressing the viral S protein, which is necessary for the initial virus attachment. Lastly, monoclonal antibodies against the SARS-CoV are being developed for possible use in post-exposure prophylaxis, and have proven highly effective when studied in vitro.
Fig. 3.17 Electron micrograph of human metapneumovirus collected from the supernatant of rhesus monkey kidney (LLC-MK2) cell culture. A virionreleasing nucleocapsid is shown. (Courtesy of CDC.)
hMPV is an enveloped single stranded, negative-sense RNA virus that represents the first mammalian virus in the metapneumovirus genus (Fig. 3.17). This genus previously contained a single member: the avian pneumovirus formerly know as turkey rhinotracheitis virus. Although there is a close phylogenetic relationship between the human and avian viruses, hMPV is unlikely to be of the same origin. When investigated, it was unable to infect turkeys or chickens in experimental models, suggesting that it is a true human virus and not a zoonotic crossover infection from birds. Genomic sequencing studies have also revealed at least two major groups of hMPV, A and B, both of which can cause human disease and circulate at the same time in a given season.
Emerging viral respiratory illnesses
Epidemiology Although the hMPV was recently isolated, serologic surveys suggest that it has been circulating in the human population since the 1950s. Delays in its identification are thought to have been due to the indistinct nature of associated symptoms, and the non-standard techniques necessary for its isolation. Reports from several countries indicate widespread prevalence of this pathogen with seasonal variation that is different in different parts of the world. Cases of hMPV are usually identified in late winter to early spring in Europe and America, and in late spring to early summer in Asia (Fig. 3.18). The organism is transmitted by close contact with contaminated secretions, such as aerosolized particles, droplets, or fomites. hMPV has been detected in patients of all ages, but predominantly in infants, children, and young adults. Several studies have suggested that hMPV may be second only to respiratory syncytial virus (RSV) as a cause of respiratory tract infections in children.
Clinical features The clinical manifestations associated with hMPV infection are variable, but fall upon the same spectrum of disease as most viral respiratory pathogens that include mild upper respiratory tract symptoms, bronchitis, bronchiolitis,
20 18 16 14 12 10 8 6 4 2 0
pneumonia, and ARDS. In addition, hMPV may play a role in acute asthma and chronic obstructive pulmonary disease (COPD) exacerbations. Although the range of clinical syndromes is broad, most illnesses appear to be minor and self-limited, particularly in the immunocompetent host. An incubation period of 3–5 days is usually followed by a constellation of symptoms. In children the most frequent are fever, rhinitis, cough, and wheezing (Fig. 3.19). The clinical diagnosis is most commonly bronchiolitis, followed by croup, asthma exacerbation, and pneumonia. The hospitalization rate in children is approximately 2%, and severe disease has been associated with coinfection with RSV. Rates of infection with hMPV among adults are highest in the younger population, presumably due to increased exposure to children. The infected young adult is often asymptomatic, or has a mild illness that does not require medical attention. In adults presenting to a physician, the spectrum of disease is similar to that described in children except for increased rates of hoarseness in the young and dyspnea in the elderly (Fig. 3.20). As for hospitalized patients, the most common admitting diagnoses are COPD or asthma exacerbations, followed by bronchitis and pneumonia. Severe infections in the adult population are seen primarily in the elderly or immunocompromised hosts. The clinical diagnosis of this pathogen is difficult since
Fever Congestion Rhinorrhea Hoarseness Cough Dyspnea Wheezing
Study break
0
20
40 60 Percentage
80
100
Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May
Percent of all patients
64
2000
2001
2002
Fig. 3.18 Seasonal variation of respiratory viruses in Finland; N=293 hospitalized children. Respiratory syncytial virus (red), rhinovirus (blue), enterovirus (green), and human metapneumovirus (brown) during the study period. (Adapted from CDC data.)
Fig. 3.19 Common symptoms at presentation in children infected with human metapneumovirus. (Compiled data from Boivin G, et al., 2002, 2003; Peiris JS, et al. (C), 2003; van den Hoogen BG, et al., 2001; Esper F, et al., 2003; Williams JV, et al., 2004.)
Emerging viral respiratory illnesses 65
syndromes associated with hMPV are virtually indistinguishable from those associated with other common viruses including RSV, parainfluenza, influenza, and
adenovirus. Chest imaging has also been found to be nonspecific, with a number of possible findings. Illustrative cases are shown in Figs. 3.21–3.25.
Fever Constitutional Sx Congestion Rhinorrhea Sore throat Hoarseness Cough Sputum Dyspnea Wheezing
0
20
40 60 Percentage
80
100
Fig. 3.20 Common symptoms at presentation in adults infected with human metapneumovirus. (Constitutional Sx: constitutional symptoms; a combination of a few of the following: loss of appetite, fatigue, generalized weakness, decreased energy levels, and weight loss.) (Compiled data from Boivin G, et al., 2003; Falsey AR, et al., 2003.)
Fig. 3.21 A 6-month-old infant with human metapneumovirus bronchiolitis. Chest radiograph shows hyperinflation and diffuse perihilar infiltrates. (From Williams JV, et al., 2004.)
A 3.22 High resolution computed tomography of the chest in a 58-year-old man, known to have acute myeloid leukemia, who developed human metapneumovirus pneumonia 40 days after receiving an allogeneic hematopoietic stem cell transplant. A: A small nodule surrounded by a halo of ground-glass attenuation is present in left upper lobe (arrow). A nodular opacity is also seen in the right upper lobe (arrowhead). B: Multiple subpleural lung nodules are present in the left lower lobe. Bronchiolar wall thickening and poorly defined centrilobular nodules are seen in the middle (black arrow) and right lower (white arrows) lobes. Also seen are bilateral subpleural areas of ground-glass opacification. (From Franquet T, et al., 2005.)
B
66
Emerging viral respiratory illnesses
A
B
Fig. 3.23 High resolution computed tomography of chest of a 58-year-old male with a history of acute myeloid leukemia, who developed human metapneumovirus pneumonia 80 days after receiving an allogeneic hematopoietic stem cell transplant. A: Poorly defined nodules present in both lungs (arrows). Also seen are bilateral subpleural areas of groundglass opacification. B: Multiple centrilobular nodules (arrows), a few branching opacities (tree-in-bud pattern, short arrows), and focal areas of consolidation (asterisk) with adjacent ground-glass opacification in the left lower lobe. (From Franquet T, et al., 2005.)
A
B
C
D
Fig. 3.24 Computed tomography (CT) images of chest of a 44-year-old male with acute myeloid leukemia and human metapneumovirus pneumonia, who developed acute respiratory distress syndrome and spontaneous pneumomediastinum 60 days after receiving an allogeneic hematopoietic stem cell transplant. A: Bilateral and multiple lobular areas of groundglass attenuation in both lungs (arrows). B: Bilateral perihilar areas of consolidation. C: One week after scan in B, shows extensive pneumomediastinum (arrows). A small cyst is also seen in the right upper lobe (arrowheads). D: Follow-up CT scan obtained 2 months after the scan in C shows residual architectural distortion (arrows) and fibrosis. (From Franquet T, et al., 2005.)
Emerging viral respiratory illnesses 67
A B Fig. 3.25 Pathologic findings of lung tissue sections from a previously healthy 40-year-old man who presented with acute pneumonia during the outbreak of SARS in southern China. He died in 8 days from respiratory failure. Human metapneumovirus was the only pathogen isolated in the post-mortem examination. A: Pulmonary congestion and edema C D (H&E stain, original magnification x100). B: A mild degree of interstitial lymphocytic infiltration. Intra-alveolar organizing exudative lesion was occasionally found. Detached atypical pneumocytes are indicated by the arrow (H&E stain, original magnification x200). C: Atypical multinucleated pneumocytes were occasionally identified. Definite viral inclusion was not apparent (H&E stain, original magnification x400). D: Fibrin thrombi were frequently noted in small pulmonary arteries and arterioles (H&E stain, original magnification x200). (Courtesy of CDC.)
Laboratory diagnosis
Treatment
Diagnosis of hMPV may be undertaken using several methods. Serologic testing can be performed using ELISA or virus neutralizing antibodies. Since seropositivity is estimated to be close to 100% by the age of 5 years, serologic diagnosis has been based on either seroconversion or a greater than fourfold increase in antibody titers over time. RT-PCR is the most sensitive tool for diagnosis, but is not yet widely available. Lastly, culture and isolation of hMPV are well known to be difficult. Initial studies identified the rhesus monkey kidney cells (LLC-MK2) as the most sensitive growth medium for this organism; however, more recent reports suggest that when used in combination with universal RT-PCR, culture on human laryngeal cancer cells (HEp-2) may be more sensitive.
Treatment is supportive. To date, no clinical data exist on the use of antiviral therapy in hMPV. However, in vitro testing has suggested activity of ribavirin against this virus.
Prevention As with any viral respiratory pathogen, standard control measures should be applied, particularly in a hospital setting. Consideration may be given to separating patients with known RSV from those with hMPV given the risk of severe disease. Experimental vaccines using parainfluenza vectors are currently being tested on animal models. Initial studies are promising.
68
Emerging viral respiratory illnesses
Avian influenza Background Recently, several avian influenza viruses have been reported to cause infections in humans through direct bird-to-human contact. The most striking of these are a series of outbreaks, the first of which occurred in Hong Kong in 1997 caused by a highly pathogenic strain of influenza A, namely H5N1. This virus has received attention worldwide due to the severe illness it causes in humans, its predilection for the young, and strikingly high mortality rates. Since the fall of 2003, this strain has spread throughout Asia, causing an endemic in poultry, infecting a gradually growing number of humans and thus, causing mounting concerns for an impending pandemic.
Virology Influenza viruses are classified into types A, B, and C. While types B and C typically occur in humans, type A can infect birds as well as a few mammals including humans. These viruses belong to the Orthomyxovirus family. The influenza A virus, in particular, is an enveloped organism containing 8 segments of negative stranded RNA. The envelope is internally lined by a matrix protein (M), and externally with two surface proteins: a rod-shaped hemagglutinin protein (HA) and a mushroom-shaped neuroaminidase protein (NA), of which there are 15 (H1–15) and nine (N1–9)
A
distinct subtypes respectively. The latter two proteins are responsible for the antigenic definition of the different virus subtypes and are included in the WHO nomenclature of each virus (Fig. 3.26). All subtypes of influenza A can infect birds; however, of the 15 known avian subtypes essentially H5, H7, and H9 have been implicated in direct bird-tohuman spread and secondary human disease. The influenza A virus and its strains are constantly evolving secondary to antigenic variation in the genes encoding for HA and NA. There are two described mechanisms by which these changes occur: antigenic drift and antigenic shift (Fig. 3.27A, B). An antigenic drift is a process in which point mutations occur due to inefficient ‘proof-reading’ at some stage in viral RNA transcription, leading to accumulation of new antigenic variants, which allows the virus to evade the host’s immune defenses and secondarily give rise to yearly epidemics. On the other hand, an antigenic shift is a process by which new strains are formed. These novel viruses are produced when human and avian subtypes coinfect the same intermediate host, usually swine, ‘swap’ or ‘reassort’ RNA segments, resulting in a human virus with new surface proteins to which the population is immunologically naïve; hence, affording a high potential for outbreaks and pandemics.
Fig. 3.26 Influenza A. A: Structure of influenza A virion. B: Transmission electron micrograph, negative stain image of the influenza A virus. (Courtesy of CDC.)
B HA gene HA antigen (1-15) NA antigen (1-9)
NA gene
A/chicken/HongKong/258/97 (H5N1) Virus type
Host if not Geographic human origin
Strain number
Year of isolation
Virus subtype
Emerging viral respiratory illnesses 69
Fig. 3.27A Illustration of antigenic drift. (Adapted from NIAID data.)
1 Each year’s flu vaccine contains three flu strains – two A strains and one B strain – that can change from year to year 2 After vaccination, your body produces infection-fighting antibodies against the three flu strains in the vaccine Antibody
3 If you are exposed to any of the three flu strains during the flu season, the antibodies will latch on to the viruses’s HA antigens, preventing the flu virus from attaching to healthy cells and infecting them 4 Influenza virus genes, made of RNA, are more prone to mutations than genes made of DNA Viral RNA
Mutation
5 If the HA gene changes, so can the antigen that it encodes, causing it to change shape
HA gene HA antigen
6 If the HA antigen changes shape, antibodies that normally would match up to it no longer can, allowing the newly mutated virus to infect the body’s cells
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The genetic change that enables a flu strain to jump from one animal species to another, including humans, is call antigenic shift. Antigenic shift can happen in three ways
Bird influenza A strain
Bird host
2 Without undergoing genetic change, a bird strain of influenza A can jump directly from a duck or other aquatic bird to humans
The new strain may further evolve to spread from person to person. If so, a flu pandemic could arise
Human influenza A strain
3 Without undergoing genetic change, a bird strain of influenza A can jump directly from a duck or other aquatic bird to an intermediate animal host and then to humans
1A A duck or other aquatic bird passes a bird strain of influenza A to an intermediate host, such as a chicken or pig
1B A person passes a human strain of influenza A to the same chicken or pig. Note: reassortment can occur in a person who is infected with two flu strains 1C When the viruses infect the same cell, the genes from the bird strain mix with genes from the human strain to yeild a new strain
Viral entry intermediate host cell
New influenza strain
Genetic mixing
Intermediate host
1D The new strain can spread from the intermediate host to humans
Fig. 3.27B Illustration of antigenic shift. (Adapted from NIAID data.)
Emerging viral respiratory illnesses 71
Epidemiology There have been three influenza A pandemics and multiple outbreaks over the past century, each of which is associated with a distinct new subtype of avian origin (Fig. 3.28). The most notable of these is the ‘Spanish Flu’, which occurred from 1918–1919 and was caused by a new subtype, the H1N1. This pandemic claimed the lives of 20–50 million people worldwide. Over half of the dead were young, previously healthy adults. This subtype (H1N1) was reintroduced to the human population in the 1970s and is currently among the subtypes which circulate in the population today.
The natural reservoir for avian influenza viruses is wild birds, particularly migratory waterfowl. These hosts are not usually susceptible to illness, but can spread the virus to domesticated birds by contaminating water resources and common grounds. The virus is then transmitted to humans or intermediate hosts through saliva, secretions, or feces (Fig. 3.29). All viral strains can be divided into two pathotypes, low (LPAI) and high (HPAI) pathogenicity, based on the severity of illness induced in poultry. Most avian influenza outbreaks among birds are of low pathogenicity, with little or no illness noted in infected birds,
Fig. 3.28 Timeline of emergence of influenza A viruses in humans.
Bird to human transmission
Pandemics (number of dead globally [millions])
Avian influenza H9
H7
H5
H5
2005
2003
1977 1998/99
1977
Russian influenza Hong Kong H1 Asian influenza influenza H3 H2
1968
1918
Spanish influenza H1
1–4
1957
20–50
1–4
Fig. 3.29 Cycle of avian influenza viruses in animals and humans.
Domestic birds
Shore birds
Mammals (primarily swine)
Waterfowl
Natural avian influenza cycle
Pandemic disease cycle
Humans
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and associated low mortality rates. Highly pathogenic strains in poultry, on the other hand, are extremely contagious, produce severe systemic illness secondary to viremia and have mortality rates of up to 100%. The strains of H5N1 now endemic in Asia belong to the highly pathogenic group. Humans at increased risk of contracting avian influenza are those with close contact to live poultry. Open air wildlife markets in which domesticated and wild animals are kept in close proximity, and frequently culled on site, are common in several parts of east Asia. These markets are often crowded and unsanitary, providing ample close contact between humans, wild and domesticated birds, promoting bird-to-bird and bird-to-human spread of infection. In addition, these markets provide a fertile breeding ground for viral coinfection and genetic reassortment in human and animal hosts (Fig. 3.30). The first known outbreak of H5N1 virus among humans
occurred in 1997 in a live market in Hong Kong, with 18 identified human cases and a mortality rate of 33%. This prompted the culling of the entire poultry population in Hong Kong comprised of greater than one million birds. This rapid response is thought to have averted a pandemic. However, in 2003 the H5N1 subtype re-emerged in two confirmed and one suspected case in Hong Kong. Since then, human outbreaks with variants of this strain have been documented in Thailand, Vietnam, Cambodia, and Indonesia (Fig. 3.31). As of October 19th 2006, the total number of reported human cases is 256 with 151 deaths. Thus far, only limited human-to-human transmission has been identified. However, the multiple H5N1 outbreaks in poultry occurring throughout the far east, and more recently Europe (Romania, Russia, and Turkey) raise concerns about genetic alteration in the current strains leading to H5 hybrid subtypes easily transmissible to humans and, hence, an imminent pandemic.
Human population Coinfected human cell
New virus strain spreads in human population
Bird population
Influenza A (human strain) New reassorted virus strain Pig population Poultry with influenza A (H5N1)
Coinfected pig cell
New reassorted virus strain
Fig. 3.30 Generation of a potentially pandemic strain of influenza through reassortment. (Adapted from Hien TT, et al., (A), 2004.)
100 90 80 70 60 50 40 30 20 10 0
Fever Headache Myalgia Rhinorrhea Sore throat Cough Sputum Dyspnea Vomiting Diarrhea Abdominal pain
Alive
Vietnam
Turkey
Thailand
Iraq
Indonesia
Egypt
Djibouti
China
Cambodia
Dead
Azerbaijan
Number of patients with H5N1
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0
20
40 60 Percentage
80
100
0
20
40 60 Percentage
80
100
Pulmonary infiltrates Lymphocytopenia
Fig. 3.31 Countries with reported human cases and fatalities from avian influenza (as of October 2006).
Thombocytopenia Increased aminotransferases
Fig. 3.32 Clinical symptoms of H5N1 infection at presentation. (Clinical and laboratory data from around 50 patients are compiled from several series, including Yuen K, et al., 1998; Chan PK, 2002; Chotpitayasunondh T, et al., 2005; Hien TT, et al., (B), 2004.)
Clinical features Clinical manifestations of infection with avian influenza viruses are similar to those seen with human influenza disease. Presentation may range from typical ‘flu-like’ symptoms such as fever, cough, sore throat, and myalgias, to more severe illnesses like pneumonia, ARDS, progression to multisystem organ failure and, ultimately, death. Clinical manifestations and severity of illness are at least in part determined by the infecting strain. Outbreaks caused by avian influenza H7 strains, for example, have been associated with high rates of conjunctivitis, while those caused by H5 subtypes have been associated with respiratory failure and high fatality rates. The full clinical spectrum of H5N1 influenza is not yet known. Thus far, reports from H5N1 influenza outbreaks revealed clinical manifestations similar to those seen in more severe cases of human influenza. The majority of affected patients were previously healthy children or adults, with an identifiable recent exposure to poultry. Estimated incubation period, based on known exposure, was from
2–4 days. Common presenting symptoms included fever and lower respiratory and gastrointestinal tract symptoms (Fig. 3.32). Clinically, infected individuals deteriorated rapidly, and most required mechanical ventilation within 48 hours of admission. Risk factors associated with increased severity of disease included older age and delayed admission to hospital. Mortality rates have been estimated upwards of 50%. Laboratory studies in patients with H5N1 influenza may show lymphocytopenia, thrombocytopenia, and liver dysfunction. Radiological abnormalities are usually significant, developing within a median of 7 days from the onset of fever. A spectrum of abnormalities has been reported including interstitial or alveolar infiltrates in a focal or multilobar distribution. Progression to bilateral groundglass infiltrates compatible with non-cardiogenic pulmonary edema is often seen. Illustrative cases are shown in Fig. 3.33 and Fig. 3.34.
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A
B
Fig. 3.33 Chest radiograph of a 39-year-old woman presenting with rapidly progressive pneumonia 1 week after onset of fever and diarrhea. A: Chest radiograph on hospital day 5 shows patchy infiltration at bilateral lower lung fields. B: Chest radiograph 24 hours later shows rapidly progressive pneumonia in both lung fields, compatible with adult respiratory distress syndrome. (Courtesy of CDC.)
A
B
C
D
Fig. 3.34 Histopathologic and immunohistochemical evidence of avian influenza A (H5N1) virus in leopard lung. A: Diffuse alveolar damage in the lung: alveoli and bronchioles (between arrowheads) are flooded with edema fluid and inflammatory cells. B: Inflammatory cells in alveolar lumen consist of alveolar macrophages (arrowhead) and neutrophils (arrow). C: Many cells in affected lung tissue express influenza virus antigen, visible as brown staining. D: Expression of influenza virus antigen in a bronchiole is visible mainly in nuclei of epithelial cells.
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Diagnosis Avian influenza infection should be considered in any patient presenting with an acute febrile illness, with recent travel to areas with documented H5N1 endemic in its poultry flock (Table 3.9). Standard laboratory testing for all suspected cases of influenza include rapid antigen tests, RTPCR, viral isolation in cell cultures, and serology. An ideal specimen for laboratory testing is usually a nasopharyngeal aspirate obtained within 3 days of onset of symptoms. Unlike human influenza A, the diagnostic yield of pharyngeal swabs is higher than nasal ones, given the at least 10-fold increase in the viral load in the former location. Although rapid antigen testing is less sensitive than RTPCR or viral isolation in detecting influenza A, particularly when H5N1 is the infecting strain, it is often helpful in the initial assessment. However, further testing is needed to identify the subtype. This can be accomplished by using immunofluorescence (IF) assays with specific monoclonal antibodies on collected or cultured specimens, hemagglutination-inhibition (HAI) of cell culture medium, or RTPCR. There are few cell lines that will grow H5 strains in culture; the Madin-Darby Canine Kidney (MDCK) cell line is the preferred one (Fig. 3.35). Lastly, serologic testing for subtype determination is least useful in acute diagnoses, since antibodies require at least 14 days from onset of illness to increase. A titer is considered positive if a fourfold increase is demonstrated in the convalescent phase.
Table 3.9 Countries with influenza A H5N1 outbreaks in poultry and wild birds
Reported in 2003 • Cambodia • China • Indonesia • Japan • Russia • South Korea • Thailand • Vietnam
Reported in 2004 • Laos • Malaysia • Mongolia Reported in 2005 • Kazakhstan • Romania • Russia • Turkey
Treatment
Prevention
The care is mainly supportive. The Food and Drugs Administration has approved the use of four antiviral drugs in the management of influenza viruses: amantadine, rimantadine, oseltamivir, and zanamivir. Current recommendation for suspected H5N1 influenza is for the use of the neuroaminidase inhibitors, since H5N1 strains from the most recent outbreaks have demonstrated drug resistance to amantadine and rimantadine, but susceptibility to oseltamivir and zanamivir. The optimal dose and duration of therapy are not yet known. It is believed, however, that early administration of oseltamivir is associated with reduction in viral shedding, and perhaps improved outcome.
Surveillance within the bird population continues. Consideration is being given to the widespread vaccination of birds. Preventative measures for those with close contact with poultry should include contact precautions such as masks and gloves, frequent and thorough hand washing, and vaccination against seasonal flu. There have been no known cases of the spread of influenza virus through consumption of poultry. However, raw poultry should be handled hygienically, and cooked to temperatures greater than 70ºC well prior to consuming. Phase 1 vaccine trials are currently underway. Prophylaxis with oseltamivir has been recommended for those with known, or expected high-risk exposure.
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Collect nasopharyngeal specimen
Rapid antigen detection by influenza A-specific monoclonal IF
Positive
Virus isolation in MDCK cells
Cytopathic effect
Negative
H5 monoclonal Ab IF H5 specific RT-PCR
Negative
H5 monoclonal Ab IF H5 specific RT-PCR
Positive
Positive
Negative
Case of H5N1 influenza
Fig. 3.35 Diagnostic strategy for laboratory confirmation of H5N1 infection.
Conclusions • Emerging respiratory viruses continue to threaten global health with potential pandemics. WHO, in collaboration with health authorities throughout the world, has averted the potential pandemic of SARS and hopefully avian influenza in the near future. • Knowledge of epidemiologic patterns of SARS, avian influenza, and hMPV is crucial in assessing patients with respiratory, gastrointestinal, and/or constitutional complaints. • While the symptoms produced by the above noted viruses are non-specific, the disease they induce is usually severe, often fatal in immunocompetent hosts infected with SARS-CoV and H5N1 and, to a lesser degree, immunosuppressed hosts infected with hMPV.
• Several diagnostic tests are currently available for viral isolation or detection offered only in specialized labs across the world. Consulting with these establishments early in patients’ courses is quite helpful. • Supportive care is the mainstay in management for the majority of patients. Antiviral therapy and immune modulating agents may play some role in selected groups. Infection control measures are key in containing outbreaks. Vaccines, now being developed, are essential in preventing pandemics. • One needs to keep updated on the evolution of bird flu by contacting CDC and WHO.
Emerging viral respiratory illnesses 77
References Avedano M, Derkach P, Swan S, et al. Clinical course and management of SARS in health care workers in Toronto: a case series. CMAJ 2003;168(13):1649–1660. Boivin G, Abed Y, Pelletier G, et al. Virological features and clinical manifestations associated with human metapneumovirus: a new paramyxovirus repsonsible for acute respiratory-tract infections in all age groups. J Infect Dis 2002;186(9):1330–1334. Boivin G, DeSerres G, Cote S, et al. Human metapneumovirus infections in hospitalized children. Emerg Infect Dis 2003;9(6):634–640. Booth CM, Matukas LM, Tomlinson GA, et al. Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area. JAMA 2003;289:2801–2809. Chan JWM, Ng CK, Chan YH, et al. Short term outcome and risk factors for adverse clinical outcomes in adults with severe acute respiratory syndrome (SARS). Thorax 2003;58:686–689. Chan PK. Outbreak of avain influenza A (H5N1) virus infection in Hong Kong in 1997. Clin Infect Dis 2002;34:Suppl2:S58–S64. Chan PK, Ip M, Ng KC, et al. Severe acute respiratory sundromw-associated coronavirus infection. Emerg Infect Dis 2003;9(11):1453–1454. Chotpitayasunondh T, Ungchusak K, Hanshaoworakul W, et al. Human disease from influenza A (H5N1), Thailand, 2004. Emerg Infect Dis 2005;11:201–209. Donnelly CA, Ghani AC, Leung GM, et al. Epidemiology determinants of spread of causal agent of severe acute respiratory syndrome in Hong Kong. Lancet (2003);361(9371):1761–1766. Esper F, Boucher D, Weibel C, et al. Human metapneumovirus infection in the United States: clinical manifestations associated with a newly emerging respiratory infection in children. Pediatrics 2003; 111(6 Pt 1):1407–1410. Falsey AR, Erdman D, Anderson LJ, et al. Human metapneumovirus infections in young and elderly adults. J Infect Dis 2003;187(5):785–790. Franquet T, Rodriguez S, Martino R, et al. Human metapneumovirus infection in hematopoietic stem cell transplant recipients: high-resolution computed tomography findings. J Comput Assist Tomogr 2005;29(2)223–227.
Hien TT, de Jong M, Farrar J, (A). Avian influenza – a challenge to global health care structures. N Engl J Med 2004;351(23):2363–2365. Hien TT, Liem NT, Dung NT, et al., (B). Avian influenza A (H5N1) in 10 patients in Vietnam. N Engl J Med 2004;350:1179–1188. Hsu LY, Lee CC, Green JA, et al. Severe acute respiratory syndrome (SARS) in Singapore: clinical features of index patient and inital contacts. Emerg Infect Dis 2003;9(6):13–717. Lee N, Hui D, Wu A, et al. A major outbreak of severe acute respiratory syndrome in Hong Kong. N Engl J Med 2003;348:1986–1994. Leung GM, Hedley AJ, Lai-Ming Ho, et al. The epidemiology of severe acture respiratory syndrome in the 2003 Hong Kong epidemic: an analysis of all 1755 patients. Ann Intern Med 2004;141(9):662–673. Nicolaou S, Al-Nakshabandi NA, Muller NL. SARS: imaging of severe acute respiratory syndrome. Am J Roentgenol 2003;180:1247–1249. Peiris J, Ch C, Cheng V, et al. (A). Clinical progression and viral load in a community outbreak of coronavirusassociated SARS pneumonia: a prospective study. Lancet 2003;361:1767–1772. Peiris JS, Yuen KY, Osterhaus, et al. (B). The severe acute respiratory syndrome. N Engl J Med 2003;349(25);2431–2441. Peiris JS, Tang YL, Chan KH, et al. Children with respiratory disease associated with metapneumovirus in Hong Kong. Emerg Infect Dis 2003;9(6):628–633. Poutanen SM, Low DE, Henry B, et al. Identification of severe acute respiratory syndrome in Canada. N ENGL J Med 2003;348(20):1995–2005. Rainer TH, Cameron PA, Smit D, et al. Evaluation of WHO criteria for identifying patients with severe acute respiratory syndrome out of hospital: prospective observational study. BMJ 2003;326(7403):1354–1358. Tsang KW, Ho PL, Ooi GC, et al. A cluster of cases of severe acute respiratory syndrome in Hong Kong. N Engl J Med 2003;348(20):1977–1985. Tsui PT, Kwok ML, Yuen H, et al. Severe acute respiratory syndrome: clinical outcome and prognositc correlates. Emerg Infect Dis 2003;9:1064–1069.
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van den Hoogen BG, de Jong JC, Groen J, et al. A newly discovered human pneumovirus isolated from young children with respiratory tract disease. Nat Med 2001;7(6):719–724. Williams JV, Harris PA, Tollefson SJ, et al. Human metapneumovirus and lower respiratory tract disease in otherwise healthy infants and children. N Engl J Med 2004;350(5):443–450. Wong KT, Antonio GE, Hui DS, et al. Thin-section CT of severe acute respiratory syndrome: evaluation of 73 patients exposed to or with the disease. Radiology 2003;228(2):395–400. Yuen K, Chan M, Peiris M, et al. Clinical features and rapid viral disgnosis of human disease associated with avain influenza A H5N1 virus. Lancet 1998;351:467–471. Zhao Z, Zhang F, Xu M, et al. Description and clinical treatment of an early outbreak of severe acute respiratory syndrome (SARS) in Guangzhou, PR China. J Med Microbiol 2003;52(Pt8):715–720. Zhong NS, Zheng BJ, Li YM, et al. Epidemiology and cause of severe acute respiratory syndrome (SARS) in Guangdong, People’s Republic of China, in February, 2003. Lancet 2003;362(9393):1353–1358.
Further reading Beigel JH, et al. Avian influenza A (H5N1) infection in humans. N Engl J Med 2005;353(13):1374–1385. Concensensus document on the epidemiology of SARS. WHO/CDC/CSR/GAR/2003.11.Geneva. Last accessed October 20 2005 at: http://www.who.int/csr/sars/en/WHOconsensus.pdf. Leung GM, Hedley AJ, Ho LM, et al. The epidemiology of severe acute respiratory syndrome in the 2003 Hong Kong epidemic: an analysis of all 1755 patients. Ann Intern Med 2004;141(9):662–673. Levy MM, Baylor MS, bernard GR, et al. Clinical issues and research in respiratory failure from severe acute respiratory syndrome. Am J Respir Crit Care Med 2005;171(5):518–526. Peiris JS, Yuen KY, Osterhaus AD, et al. The severe acute respiratory syndrome. N Engl J Med 2003;349(25): 2431–2441.
van den Hoogen BG, de Jong JC, Groen J, et al. A newly discovered human pneumovirus isolated from young children with respiratory tract disease. Nat Me d 2001;7(6):719–724. WHO interim guidelines on clinical management of humans infected by influenza A(H5N1). Last assessed October 20 2006 at http://www.who.int/csr/disease/avian_influenza/guideline s/Guidelines_Clinical%20Management_H5N1_rev.pdf. Williams JV, Harris PA, Tollefson SJ, et al. Human metapneumovirus and lower respiratory tract disease in otherwise healthy infants and children. N Engl J Med 2004;350(5):443–450. In the Absence of SARS-CoV Transmission Worldwide: Guidance for surveillance, Clinical and Laboratory Evaluation, and Reporting Version 2. Last accessed October 20 2006 at: http://www.cdc.gov/ncidod/sars/pdf/absenceofsars.pdf. The following websites have several resources worth browsing for updates and education: http://www.who.int/csr/sars/en/ http://www.cdc.gov/ncidod/sars/ http://www.who.int/csr/disease/avian_influenza/en/ http://www.cdc.gov/flu/avian/
Chapter 4
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Tuberculosis C Scott Mahan, MD and John L Johnson, MD
Introduction
Etiology and pathogenesis
Tuberculosis (TB) is a chronic necrotizing granulomatous disease caused by Myc o b ac te rium tub e rc ulo sis and, occasionally, by two closely related species, M. bovis and M. afric anum . The global toll of TB is staggering. TB disproportionately affects poor, malnourished, and immunocompromised persons (Fig. 4.1, Tab le 4.1). Pulmonary disease is the most common manifestation of TB, but any organ can be involved including the lymph nodes, pleura, bones, joints, and central nervous system.
TB is caused by the M. tuberculosis complex, which includes M. tuberculosis, M. bovis, M. africanum, M. microti, and M. canetti; M. tuberculosis is responsible for the most disease in humans. M. tuberculosis is an obligate aerobic, non-motile bacillus that stains acid fast, meaning it retains a deep red tint after staining with carbol-fuchsin followed by washing with acid-alcohol (Fig. 4.2). Humans are the only reservoir for M. tuberculosis.
Rates per 100,000, all forms of TB 0–24 25–49 50–99 100–299 ≥300
Fig. 4.1 Estimated worldwide tuberculosis incidence rate 2004. (Adapted from WHO data.)
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Table 4.1 Persons at increased risk for developing active tuberculosis
• Human immunodeficiency virus-infected • Elderly • Immunosuppressed persons and persons receiving corticosteroids or other immunosuppressive therapy or cancer chemotherapy • Comorbidities such as diabetes mellitus, silicosis, alcoholism, and chronic renal insufficiency • Institutionalized persons in jails, prisons, nursing homes, and chronic care facilities • Health care workers • Close contacts of infectious cases of tuberculosis • Malnourished persons • Prior arrested tuberculosis as evidenced by apical scarring or fibrosis on chest radiography
Tuberculosis is spread when an infected person coughs, sneezes, or speaks creating small (1–5 μm) aerosolized droplets of bacilli that can be inhaled by another person and deposited in the new host’s alveoli. Once tubercle bacilli reach the alveoli, several different events can occur: local tissue macrophages may kill the organism and clear it before infection is established; alternatively, the bacteria may enter the macrophages, multiply, and spread via the lymphatics and the bloodstream throughout the body. Over 90% of immunocompetent individuals are able to mount an effective cell-mediated immune response and contain the initial infection, leaving only small parenchymal scars, a Ghon focus (Fig. 4.3), or no evidence of infection except for a positive tuberculin skin test. Persons who fail to mount an adequate immune response may develop progressive primary TB. Illustrative cases are shown in Figs. 4.2–4.4.
Fig. 4.2 Ziehl–Neelsen stain of sputum sample showing red acid-fast bacilli in a patient with cavitary pulmonary tuberculosis. Fig. 4.3 A calcified Ghon focus is visible in the right lower lung field with associated hilar adenopathy. The combination of a Ghon focus (arrowhead) and a calcified draining lymph node is known as a primary (Ranke) complex (arrow). These radiographic findings are consistent with resolution of primary tuberculosis infection. (Courtesy of Dr Catherine Curley.)
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Fig. 4.4 Chest radiograph showing apical scarring due to arrested tuberculosis (Simon’s foci) in an asymptomatic 55-year-old male.
HIV prevalence in TB cases, 15–49 years (%) 0–4 5–19 20–49 ≥50 No estimate
Fig. 4.5 Estimated prevalence rates of human immunodeficiency virus coinfection in patients with tuberculosis worldwide, 2004. (Adapted from WHO data.)
Global epidemiology TB is a major global health problem that has been exacerbated by poverty, poor public health infrastructure, the acquired immunodeficiency syndrome (AIDS) epidemic and the emergence of multidrug resistant TB. Worldwide, the number of TB cases increased by 1.8% annually between 1997 and 2000. The World Health Organization (WHO) estimates that one-third of the world’s population is infected with TB. In 2005, over 9 million new cases of TB and more than 2 million deaths due to TB occurred worldwide. Ninety-five percent of all TB cases and 98% of all deaths due to TB occur in persons living in developing countries. Conditions of intense overcrowding, inadequate
sanitation, malnutrition, and lack of access to medical care all contribute to the epidemic. Human immunodeficiency virus (HIV)/AIDS and TB are closely linked. HIV coinfection is the greatest risk factor known for the progression of latent TB infection to active TB (Fig. 4.5). Increasing rates of HIV coinfection in countries in sub-Saharan Africa have led to rapid increases in the incidence of TB despite the introduction of more effective TB treatment strategies. TB is the most frequent serious opportunistic infection in adults with AIDS worldwide.
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Clinical manifestations Primary pulmonary TB
Reactivation TB
Primary TB is the development of active TB soon after infection with the tubercle bacillus in the non-immune host. Most healthy individuals are asymptomatic after TB infection, and the event is marked only by the development of a positive tuberculin skin test (TST) 4–6 weeks after infection. Infants and children are more likely than adults to develop active TB after infection. About 10% of infants and children develop symptomatic primary TB heralded by mild fever, non-productive cough, and malaise. Radiologic manifestations may include hilar or mediastinal lymphadenopathy, mid- or lower-lung infiltrates, and transient pleural effusions. Among immunocompetent adolescents and adults infected with TB, only 5–10% will develop active disease, with roughly one-half of cases occurring during the first 2 years after infection. Illustrative cases are shown in Figs. 4.6–4.8.
As noted earlier, most immunocompetent individuals are able to contain their initial infection with TB. Although these individuals have an effective immune response to initial infection, small numbers of viable, slow growing bacilli remain that are walled off in granulomas (Fig. 4.9). Later in life, during periods of waning immunity, these walled off lesions can break down and lead to local and disseminated disease. The most frequent symptoms of reactivation TB in the adult include fever, anorexia, productive cough (with or without hemoptysis) for more than 3 weeks, night sweats, and malaise. Typical chest radiographic findings include upper lobe fibrocavitary lesions and infiltrates classically involving the apical and posterior segments of the upper lobes followed in frequency by involvement of the superior segments of the lower lobes. Atypical radiographic manifestations of TB in the adult include lower lobe infiltrates similar to pyogenic pneumonia and intrathoracic adenopathy. Lower lobe TB is more frequent in patients with diabetes mellitus. Illustrative cases are shown in Figs. 4.10–4.14.
Fig. 4.6 Chest radiograph of a 4-year-old child presenting with low-grade fever and non-productive cough. There is a visible parenchymal infiltrate (Ghon focus) in the right lower lung field (arrowhead) and associated right hilar lymphadenopathy (arrow). The primary (Ranke) complex consists of the parenchymal lesion and the associated enlarged ipsilateral lymph nodes. (Courtesy of Dr Charles Daley.)
Fig. 4.7 Tuberculous pneumonia with left upper lobe infiltrate in a 4-year-old with fever and progressive primary tuberculosis. (Courtesy of Dr Charles Daley.)
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Fig. 4.8 Lobar collapse due to extrinsic bronchial compression from enlarged right hilar lymph nodes and endobronchial tuberculosis in a 5-year-old child with fever and chronic cough. (Courtesy of Dr Charles Daley.)
Fig. 4.10 Left upper lung cavity in patient with reactivation tuberculosis who presents with fever, productive cough, and weight loss.
Fig. 4.9 Pulmonary granuloma (H&E, x100). Notice the area of central caseation (arrow) with a surrounding rim of lymphocytes, mononuclear cells, multinucleated giant cells, and fibrosis.
Fig. 4.11 A chest radiograph from a 38-year-old male with 1 month of fever, weight loss, and productive cough. His chest radiograph shows a right upper lobe cavitary lesion with spreading throughout the right upper lobe and into the right lower lobe. This is an example of how caseous material and tubercle bacilli from an open cavitary lesion can spread endobronchially to other areas of the lung.
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Fig. 4.12 Chest radiograph of a 48-year-old male presenting with wasting and a productive cough. It shows right upper lung involvement with a cavitary lesion and an air bronchogram.
Fig. 4.13 Chest radiograph of a 34-year-old male with intermittent fever, weight loss, and no pulmonary symptoms. He was found to have miliary tuberculosis. Although the chest radiograph may be normal in a minority of cases, it usually shows classic miliary lesions, which are diffuse 1–2 mm rounded opacities (similar in size to millet seeds) scattered throughout all lung fields. Sometimes these lesions are best seen on a lateral view. Miliary tuberculosis is due to lymphatic and hematogenous seeding of tubercle bacilli to all areas of the lungs and other organs.
Fig. 4.14 Gross view of lungs from a fatal case of miliary tuberculosis. (Courtesy of Dr Rosana Eisenberg.)
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TB in HIV/AIDS and the immunocompromised Persons infected with HIV are at an 80–100-fold increased risk for active TB after infection by the tubercle bacillus. In the immunocompetent individual, the risk of reactivation of latent TB is about 10% over the course of their lifetime; however, in an HIV-positive individual, the risk is about 8–10% per year. Early in the course of HIV, when host defenses are less impaired, patients usually present with typical upper lung field fibrocavitary disease, similar to reactivation TB in HIV-uninfected adults. In advanced
HIV/AIDS (CD4+ count 200/mm3)
Late (CD4+ ≤200/mm3)
TST
Usually positive (5 mm or greater induration)
Usually negative
Adenopathy
Uncommon
Common
Affected lung areas
Upper lobes
Lower and middle lung fields
Cavitary disease
Frequent
Uncommon
Extrapulmonary disease
15%
30–50%
Sputum AFB smear
60% positive
40% positive
Fig. 4.15 Chest radiograph of a 28-year-old male with advanced acquired immunodeficiency syndrome (CD4+ count of 80/mm3) presenting with pleuritic right-sided chest pain and productive cough. A right mid-lung field infiltrate and associated hilar adenopathy are visible.
Fig. 4.16 Multilobar disease with associated hilar adenopathy in a patient with advanced human immunodeficiency virus/acquired immunodeficiency syndrome.
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Tuberculosis
Fig. 4.17 Chest radiograph of a 35-year-old HIV-infected man with classic upper lobe fibrocavitary disease. Chest radiographic findings in patients with early HIV (CD4+ >200/mm3) are similar to findings in HIV-uninfected persons.
Fig. 4.18 Chest radiograph of the same patient as seen in Fig. 4.17 after 6 months of standard antituberculous chemotherapy showing an excellent response to therapy. Clinical response to chemotherapy is similar in both HIV and non-HIV infected persons, although the rate of recurrence after treatment is slightly higher among HIVinfected persons.
Immune reconstitution inflammatory reactions Patients starting on antituberculous chemotherapy may develop acute worsening of their symptoms or existing tuberculous lesions or new lesions; these are termed paradoxical or immune reconstitution inflammatory syndrome (IRIS) reactions. IRIS reactions occur more frequently in HIV-infected patients with TB (7–36% of patients) and are more common when highly active antiretroviral therapy (HAART) and anti-TB treatment are started at the same time. The cause of IRIS reactions is unclear, but they may be due to reconstitution of the host immune response and an increased inflammatory response to mycobacterial antigens after beginning HIV and anti-TB therapy. Most occur within 4–12 weeks after starting HAART. IRIS reactions are more common in patients with extrapulmonary TB or low CD4+ lymphocyte counts. New or worsening adenopathy, fever, and new pulmonary infiltrates or pleural effusion are the most common presentations. After excluding other opportunistic infections, non-adherence with TB treatment, and drug resistant TB, management is by treatment of symptoms. Adjunctive corticosteroids may be helpful in severe cases. HAART therapy can usually be continued. Illustrative cases are shown in Figs. 4.19–4.21.
Fig. 4.19 A 35-year-old HIV-infected man (CD4+ 100/mm3) who developed severe cervical lymphadenitis 1 month after beginning treatment for HIV and pulmonary tuberculosis. IRIS reactions most commonly occur within 4–12 weeks after beginning HAART therapy. (Courtesy of Dr Stephen Weis.)
Tuberculosis 87
Figs. 4.20, 4.21 Tuberculous pleurisy as a manifestation of IRIS presenting as recurrent fever and chest pain in a 30year-old HIV-infected man with CD4+ 30/mm3 after beginning HAART therapy. After diagnostic thoracentesis to exclude other etiologies, the patient was treated symptomatically with ibuprofen, HAART, and anti-TB treatment with resolution of the pleural effusion over the next 3 weeks. HAART therapy can be continued along with antituberculous therapy in most instances. (Courtesy of Dr Stephen Weis.)
Extrapulmonary manifestations of TB Nearly every organ can be infected with TB. Children and young adults in developing countries often present with extrapulmonary TB. In the developed world, extrapulmonary TB is more frequent in elderly patients or compromised hosts who present with reactivation TB in the setting of waning cell-mediated immunity. The incidence of extrapulmonary and disseminated TB is greatest in HIVinfected persons. Patients with extrapulmonary TB are often difficult to diagnose. A high clinical suspicion for TB must be maintained in the appropriate setting. Patients with extrapulmonary TB may present with fever and local symptoms. Tuberculin skin tests should be done but are often negative. Chest radiographs are normal in one-quarter to one-third of patients with many forms of extrapulmonary TB. Repeated smears and cultures of infected body fluids
and biopsy of affected tissues may be required for diagnosis. The following cases illustrate common forms of extrapulmonary TB (Figs. 4.22–4.34). Other forms of extrapulmonary TB include tuberculous lymphadenitis, which is the most common form of extrapulmonary TB in developing countries. Cervical lymph nodes are most commonly involved, a form of mycobacterial lymphadenitis classically called scrofula (Fig. 4.19). Involved nodes are enlarged and non-tender without local warmth or inflammation. Draining sinuses may form. Tuberculous lymphadenitis can be diagnosed by aspiration or biopsy with smears and cultures. Other less common forms of extrapulmonary TB include cutaneous lesions (multiple manifestations), adrenal TB (the most common cause of adrenal insufficiency in developing countries), and otitis.
88
Tuberculosis Fig. 4.22 Cranial magnetic resonance imaging demonstrating intracranial tuberculomas in a 45-year-old female with disseminated tuberculosis. CNS involvement has three main presentations: parenchymal masses (tuberculomas), meningitis, and spondylitis. When present, CNS tuberculomas are usually multiple (as seen here), but may be single. Often, these lesions manifest as seizures. Treatment is combination antituberculous chemotherapy. Adjunctive corticosteroids may reduce edema and decrease symptoms. (Courtesy of Dr Richard Hewlett.)
Fig. 4.23 Gross appearance of a central nervous system parenchymal tuberculoma. (Courtesy of Dr Richard Hewlett.)
Fig. 4.24 Another manifestation of central nervous system involvement is tuberculous spondylitis as seen in this 28-year-old male who presented with 1 month of neck stiffness and pain. Over the past 2 weeks he had developed weakness in both arms and had difficulty walking. The spinal magnetic resonance image shows destruction of the C5 vertebral body with an epidural abscess tracking posteriorly behind the C4–C7 vertebrae and resultant spinal cord compression. Involvement of the lumbar region of the spine is also present.
Tuberculosis 89
Fig. 4.25 Cranial magnetic resonance image of a large right-sided tuberculoma with associated mid-line shift. The patient presented with focal left leg weakness. (Courtesy of Dr Richard Hewlett.)
Fig. 4.26 A child with tuberculous meningitis. Tuberculous meningitis can present with meningeal signs, new or evolving cranial nerve palsies, lethargy, a chest radiograph consistent with tuberculosis, and cerebrospinal fluid profile of hypoglycorrhachia, elevated cerebrospinal fluid protein, and lymphocytic pleocytosis. Tuberculous meningitis is usually due to reactivation disease in the elderly, but often is a post-primary event in children.
Fig. 4.27 An 8-year-old child with tuberculous spondylitis (Pott’s disease). Tuberculous spondylitis frequently involves the anterior portion of the vertebral body with subsequent spread to the intravertebral disc and adjacent vertebral bodies. Anterior collapse with secondary posterior spinal swelling and tenderness results in the classic kyphotic gibbus deformity (arrow). The lower thoracic spine is affected most commonly, followed by the lumbar spine. Tuberculosis also may involve the large weight-bearing joints such as the hips and knees.
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Tuberculosis
Fig. 4.28 Chest radiograph of a 79-year-old female with unexplained fever, anorexia, and weight loss. Radiographic findings are consistent with miliary tuberculosis. Miliary lesions are diffuse 1–2 mm nodular lesions scattered throughout all lung fields due to lymphohematogenous seeding of the tubercle bacilli. Patients often present with generalized non-specific symptoms. Many patients have central nervous system involvement. Laboratory confirmation is frequently difficult because only about onequarter of patients are sputum smear-positive. The diagnosis often is presumptive and based on the clinical setting and radiographic findings. Definitive diagnosis often requires histologic and culture confirmation by liver, bone marrow, or transbronchial lung biopsy.
Fig. 4.29 Radiograph of a retrograde pyelogram of a 65year-old patient with weight loss and pyuria. Findings are consistent with a diagnosis of genitourinary tuberculosis. Multiple ureteric strictures, dilated minor calices, and poor definition of the renal papillae are present. Many patients with renal tuberculosis have evidence of pulmonary tuberculosis. Sterile pyuria is suggestive of renal tuberculosis. Intravenous pyelograms or retrograde pyelograms are usually abnormal, often showing papillary necrosis, ureteral strictures (arrow), hydronephrosis, and focal calcification. Infection can spread from the initial renal foci to involve the prostate, seminal vesicles, epididymis, and testes in men. Women may have involvement of the endometrium, ovaries, cervix, and vagina.
Figs. 4.30, 4.31 Chest radiographs of a child with tuberculous pericarditis before and after treatment. Tuberculous involvement of the pericardium is usually caused by extension from a nearby draining focus of infection, such as hilar or mediastinal lymph nodes, the lung, spine, or sternum. Less commonly, it arises from hematogenous seeding. Tuberculous pericarditis usually responds well to antituberculous therapy, but drainage or surgical management may be required if there is tamponade or restriction. Adjunctive corticosteriod therapy is beneficial.
Tuberculosis 91
Fig. 4.32 Abdominal computed tomography scan showing tuberculous involvement of the ileocecal region of the gastrointestinal tract (tuberculous typhlitis). This patient had been mistakenly treated for ulcerative colitis for 6 months. Gastrointestinal tuberculosis usually arises due to the swallowing of infected pulmonary secretions with secondary seeding of the gastrointestinal tract. Tuberculosis can involve any portion of the tract with the ileocecal region being most common. Symptoms are varied, most commonly diarrhea and abdominal pain. Cecal tuberculosis can be mistaken for inflammatory bowel disease, thereby delaying treatment and risking exacerbation by the use of corticosteroids or other immunosuppressive therapy without antituberculous treatment. Patients can also have tuberculous peritonitis due to spread from adjacent tuberculous foci into the peritoneum. Laparoscopic or open peritoneal biopsy is often required to make this diagnosis.
Fig. 4.34 Right lateral decubitus chest radiograph of same patient as in Fig. 4.33. Pleural tuberculosis can be due to direct extension, hematogenous seeding, or from rupture of a subpleural caseous focus into the pleural space. Thoracentesis and pleural biopsy with smears, cultures, and histologic examination of biopsy tissue are the most useful diagnostic tests.
Fig. 4.33 Chest radiograph of a 33-year-old male with a right-sided pleural effusion secondary to tuberculosis. He presented with right-sided pleuritic chest pain, nonproductive cough, and anorexia.
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Tuberculosis
Diagnosis Latent TB TST is used in epidemiological surveys to evaluate the prevalence of TB infection in populations, and for the diagnosis of latent tuberculous infection (Fig. 4.35). A positive tuberculin skin test indicates prior tuberculous infection. TST is recommended for groups at high risk of TB infection or for developing active TB (Table 4.1). The sensitivity and susceptibility of the TST varies according to the population being evaluated (Table 4.3). Most people with a TST greater than 10 mm are infected with M. tub erculo sis. In immunocompromised or HIV-infected persons and close contacts of infectious TB cases, a 5 mm cut-off is used. False-negative and false-positive tests occur, often influenced by host characteristics such as malnutrition, immunodeficiency, and environmental exposure to non-tuberculous mycobacteria. Prior Bacille Calmette–Guérin (BCG) vaccination in infancy generally has little effect on the size of TST reactions in adulthood. TST reactions in the BCG-vaccinated adult should be interpreted the same as in non-BCG vaccinated individuals. New in vitro tests based on production of interferon-γ by sensitized lymphocytes in the presence of specific mycobacterial antigens are now becoming clinically useful. These tests use mycobacterial antigens found in M. tuberculosis, but not in most other non-tuberculous bacteria or BCG, enhancing the specificity of these tests. They have the added advantages of being done during a single visit, having no boosted responses, and little intraobserver variability. The full role of these new tests, particularly in immunosuppressed patients such as those with HIV infection, needs to be further defined.
Table 4.3 Interpretation of positive results for the tuberculin skin test in at-risk populations
≥5 mm induration • HIV infected • Close contact with someone who has tuberculosis • Chest X-ray changes suggestive of previous tuberculosis (fibrotic changes, calcifications, apical scarring) • Organ transplant recipients, patients taking tumor necrosis factor-alpha inhibitors, patients receiving immunosuppressive agents (e.g. prednisone >15 mg/d or equivalent) ≥10 mm induration • Recent immigrant from high-prevalence country • Injection drug use • High-risk groups (silicosis, diabetes, chronic renal failure, or other chronic medical conditions) • Resident or employee of prison, nursing home, homeless shelter ≥15 mm induration • Persons not in any of the above high-risk groups
Fig. 4.35 This picture shows the proper placement of the Mantoux tuberculin skin test. Purified protein (PPD) is a commercially available mixture of tuberculin antigens whose potency is adjusted using an international standard. Skin testing is performed by the intradermal injection of 0.1 ml of PPD containing 5 tuberculin units of PPD-S or 2 tuberculin units of PPD RT-23 antigen into the skin of the flexor surface of the forearm. The injection should immediately raise a wheal. The test should be read 48–72 hours later. The greatest diameter of palpable induration of the skin should be recorded in millimeters. (Courtesy of CDC.)
Tuberculosis 93
Laboratory diagnosis The diagnosis of TB is made by demonstrating the presence of tuberculi bacilli or their genomic products in smears, cultures, or from other sources of infected tissue. There is no accurate blood test for the diagnosis of TB. Sputum microscopy and culture are the most common diagnostic tests done worldwide. At least three sputum samples should be obtained, preferably in the morning when the sputum bacillary load is greatest. In those unable to produce adequate sputum samples, induced sputums with hypertonic saline, morning gastric aspirates, or bronchoscopy with lavage can be performed. When bronchoscopy is done, transbronchial biopsies can be performed for culture and histology. Other involved tissues such as lymph nodes can be sent for stains, culture, and histologic evaluation. In miliary TB, sputum smears and cultures are usually negative and diagnosis is made from culture and histology of liver, bone marrow, or transbronchial lung biopsy. Mycobacteria are notable for their acid-fastness. Staining may be performed by hot Ziehl–Neelsen stain or cold Kinyoun methods (Fig. 4.36). In the Ziehl–Neelsen method, a fixed smear covered with carbol-fuchsin is heated, rinsed, decolorized with acid-alcohol, and then counterstained with methylene blue. The Kinyoun stain is modified to make heating unnecessary. Tubercle bacilli appear as slightly bent, beaded rods 2–4 μm long. One to ten thousand tubercle bacilli per milliliter must be present in a sample for a consistently positive smear. Many large laboratories use fluorochrome stains with auramine and a counterstain (Fig. 4.37) resulting in fluorescence of the bacilli. Fluorochrome staining allows
rapid screening of large numbers of slides at lower magnification with good sensitivity. In the appropriate clinical setting, a positive smear makes TB highly likely, but culture is required for definitive diagnosis and drug susceptibility testing. Several media support the growth of tubercle bacilli. Eggbased Löwenstein–Jensen (Fig. 4.38) and clear agar-based Middlebrook media are two of the most popular. M. tuberculosis is a slow growing organism (dividing time 12–18 hours) and it may require several weeks before colonies are visible on solid media. Cultures should be examined weekly until positive or for a total of 8 weeks. Organisms from culture can then be speciated to identify them as M. tuberculosis or atypical mycobacteria using biochemical, morphologic, and genomic methods. Drug susceptibility requires an additional 2–4 weeks to complete using conventional methods. Enriched liquid culture systems such as the mycobacterial growth indicator tube (MGIT) system are becoming more widely used. These liquid culture systems are able to detect metabolically active mycobacteria more quickly than waiting for visible colonies to appear on solid media, and significantly shorten the time until cultures turn positive. Rapid tests based on nucleic acid amplification methods such as polymerase chain reaction (PCR) have been developed for diagnosis and speciation of mycobacteria. These methods are more expensive, require special equipment, and have decreased diagnostic sensitivity in patients with smear-negative disease.
Fig. 4.36 Photomicrograph of positive Kinyoun stain of a sputum smear showing numerous acid-fast bacilli. (Courtesy of Dr Rosana Eisenberg.)
Fig. 4.37 Positive sputum smear stained with fluorescent auramine with rhodamine counterstain. (Courtesy of Dr Rosana Eisenberg.)
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Fig. 4.38 Growth of bread crumb-like colonies of M. tuberculosis on Löwenstein–Jensen slant. This egg-based agar is the most common medium used worldwide for mycobacterial cultures.
Person with clinical or epidemiological risk factor for TB
No
Yes
Place tuberculin skin test
No tuberculin test recommended (if test is performed without indication, positive ≥15 mm)
Negative
Positive (by criteria, see Table 4.3)
High-risk exposure within 3 months
Chest radiograph Clinical evaluation
No
Treatment of latent infection not indicated
Yes
Normal chest radiograph
Evaluate patient for treatment of latent infection
Fig. 4.39 Algorithm for the evaluation of persons with suspected TB infection.
Abnormal chest radiograph or patient has symptoms (fever, cough, weight loss)
Evaluate patient for active TB
Tuberculosis 95
Susceptibility testing of strains of TB can be performed conventionally by evaluating critical concentrations of drugs required for inhibition of growth on solid media. A drawback of these methods is that they take an additional 2–4 weeks to perform after a positive culture is obtained. This delay can be substantially reduced using enriched liquid culture systems. In addition, rapid PCR-based methods have been developed to detect rifampicin resistance, based on detection of frequent mutations of the bacterial RNA polymerase. Other rapid susceptibility tests are in development.
Fig. 4.40 Chest radiograph showing extensive tuberculosis of the left lung with a large upper lung field cavity in a 40-year-old male with smear-positive tuberculosis.
Fig. 4.41 The same patient as seen in Fig. 4.40 after completing antituberculous therapy. Note the healing of cavitary lesion and scarring and fibrosis, with retraction of the trachea to the left.
Radiographic diagnosis In addition to sputum microscopy and culture, chest radiography is commonly done in patients with suspected TB (Fig. 4.39). Active pulmonary TB classically presents with upper lobe involvement on one or both lungs. The apical and posterior segments of the upper lobes are most commonly affected. Active TB is suggested by consolidation, nodular infiltrates, and cavitation. These findings in the right clinical context are highly suggestive of TB although other diseases such as histoplasmosis, aspergillosis, sarcoidosis, and atypical mycobacterial infections can present with similar findings. Illustrative cases are shown in Figs. 4.40–4.43.
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Fig. 4.42 Extensive bilateral patchy infiltrates and a left upper lung cavitary lesion in an adult with tuberculosis infected with human immunodeficiency virus.
Fig. 4.43 Chest radiograph of the patient seen in Fig. 4.42 after completing antituberculous therapy.
Management Combination chemotherapy using the directly observed therapy, short course (DOTS) approach is the standard for TB treatment worldwide, and is highly successful and costeffective. Treatment of patients with drug-susceptible TB with 6 months of chemotherapy using isoniazid (INH), rifampicin, ethambutol, and pyrazinamide for 2 months followed by treatment with INH and rifampicin for 4 months is effective in over 95% of cases when fully administered using the DOTS approach. The DOTS approach (Fig. 4.44) is a comprehensive case management strategy including regular, supervised administration of antiTB drugs, a steady supply of high-quality drugs, systematic
recording of treatment outcomes, and commitment by governments, TB control programs, and caregivers to cure patients with TB. TB is treated with a combination of drugs with different mechanisms of action for a minimum of 6–9 months (Table 4.4). Active TB should never be treated with a single drug, and a single drug should never be added to a failing regimen because of the risk of emergence of drug resistance. Six months of treatment is recommended for patients with drug susceptible disease (Table 4.5). Patients with cavitary pulmonary TB whose sputum cultures are still positive after the first 2 months (intensive phase) of treatment should have
Table 4.4 Dosages of first-line antituberculosis drugs
Drug
Daily dose (maximum dose)
Thrice weekly dose (maximum dose)
Isoniazid
5 mg/kg (300 mg)
10 mg/kg (900 mg)
Rifampicin
10 mg/kg (600 mg)
10 mg/kg (600 mg)
Pyrazinamide
25 mg/kg (2000 mg)
35 mg/kg (3000 mg)
Ethambutol
15 mg/kg (1600 mg)
30 mg/kg (4000 mg)
(Adapted from WHO guidelines, 2004)
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DOTS population coverage (%) Not implementing 10,000
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Malaria
Management Antimalarial drugs are the mainstay of treatment for malaria (Figs. 5.15, 5.16). Treatment depends on which Plasmodium species is causing the infection, the geographic area of acquisition (due to prevalence of drug resistance), and the severity of symptoms (requiring parenteral or oral therapy). Tables 5.2 and 5.3 outline the current guidelines for treatment of P. falciparum infection. Treatment for most P. vivax (except in parts of Asia) and P. ovale infection involves a course of chloroquine, followed by 14 days of
primaquine to eradicate liver hypnozoites that cause relapse. P. malariae is usually treated with chloroquine only. In cases of high-level parasitemia, rapid initiation of antimalaria medication is needed. In addition, exchange transfusion should be considered because infection-related progressive hemolytic anemia may be life threatening. The US Centers for Disease Control and Prevention (CDC) has a malaria hotline with recommendations for malaria treatment at (404)332-4555 or www.cdc.gov.
Table 5.2 Drug treatment of severe Plasmodium falciparum malaria
Drug Quinidine gluconate
Adult dosage 10 mg/kg loading dose IV over 1–2 hr followed by basal 0.02 mg/kg/min until oral therapy can be started
Pediatric dosage Same as adult
Comments Continuous EKG, blood pressure, and glucose monitoring are needed
Quinine dihydrochloride
20 mg/kg loading dose in 5% dextrose IV over 4 hr followed by 10 mg/kg over 2–4 hr q 8 hr (max 1800 mg/d) until oral therapy can be started
Same as adult
Not available in the US but common in other countries. Adverse effects include hypoglycemia, tinnitus, dizziness, and gastrointestinal disturbances
Artemether
3.2 mg/kg IM, then 1.6 mg/kg daily x5–7 d
Same as adult
Not available in the US
(Adapted from Drugs for Parasitic Infections. Med Lett Drugs Ther August 2004; Epub:1. Available online at www.medicalletter.org)
Fig. 5.15 Dispensing antimalarial medications during a treatment time-to-reinfection study among Papua New Guinean school children.
Fig. 5.16 Antimalarial medications in a rural Kenyan clinic. Less than optimal storage conditions may limit potency and efficacy of available drugs.
Malaria 109
Table 5.3 Oral drug treatment for uncomplicated Plasmodium falciparum malaria Drug
Adult dosage
Pediatric dosage
Comments
Quinine sulfate plus Doxycycline or Tetracycline or Pyrimethamine-sulfadoxine
650 mg q 8 hr x3-7 d 100 mg q 12 hr x7 d 250 mg q 6 hr x7 d 3 tablets on last day of quinine
30 mg/kg/d div q 8 hr x3-7 d 4 mg/kg/d div q 12 hr x7 d 6.25 mg/kg q 6 hr x7 d 40 kg: 1 tablet
Beginning 1–2 days before travel, continuing through travel time and for 7 days after leaving malaria-endemic areas. Pediatric tablets are available. 1 pediatric tablet = 1/4 adult tablet
Doxycycline
100 mg PO daily
2 mg/kg/d (max 100 mg)
Adverse effects include photosensitivity. Not for use in children 99% of pseudomembranous colitis (Figs. 6.3, 6.4), and the leading cause of diarrhea in hospitalized patients. In most cases, CDAD produces an inflammatory diarrhea, with the stool positive for fecal leukocytes (Fig. 6.5). Recent reports have provided evidence of an epidemic of CDAD in North America1. The study from Sherbrooke, Quebec is the most recent large study to examine the population-based incidence of CDAD. The authors demonstrate an increase in the incidence of
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Diarrheal disease
Fig. 6.1 Gram stain of Clostridium difficile demonstrating Gram-positive, spore-forming rods. C. difficile-associated diarrhea is epidemic in hospitals in North America. (Courtesy of Dr D Bobak.)
Fig. 6.2 Spores of Clostridium difficile. The spores play an important role in hospital epidemics as they may exist for long periods of time in harsh environmental conditions in the hospital, and patients may become colonized. (Courtesy of Dr R Salata.)
Fig. 6.3 Endoscopic examination revealing psueodomembranes. Pseudomembraneous colitis occurs in a subset of patients with Clostridium difficile-associated diarrhea (CDAD). Lower endoscopy revealing pseudomembranes is pathognomonic for CDAD. (Courtesy of Dr R Salata.)
1
1
Fig. 6.4 CT scan showing dilated and thickened colon (arrow, colon wall; 1, pericolonic fat). Most patients with Clostridium difficile-associated diarrhea (CDAD) do not have pseudomembranes, but when they are seen on a CT in a patient with CDAD the appearance on the CT scan can establish the diagnosis. (Courtesy of Dr R Salata.)
Diarrheal disease 119
Fig. 6.5 Stool prep showing abundant fecal leukocytes from a patient with Clostridium difficile-associated diarrhea (CDAD). Fecal leukocytes are usually present in CDAD, and in patients with inflammatory colitis from bacterial pathogens such as Salmonella, Campylobacter and Shigella. Pathogens that produce illness without producing intestinal inflammation are not associated with fecal leukocytes. Pathogens that typically produce diarrheal illness without fecal leukocytes include viruses, enterotoxigenic Escherichia coli, cholera, Giardia, Cryptosporidium, and Cyclospora. (Courtesy of Dr R Salata.)
CDAD over the past decade, with a striking increase in the number of cases in elderly patients in 2003. Their report also provides evidence that the mortality associated with CDAD has increased, particularly among the elderly. Increasing nosocomial spread, changing patterns of antibiotic use, spread of more pathogenic C. difficile strains, and higher numbers of immunocompromised patients are cited as reasons for the increase. The authors also reported evidence that CDAD may be becoming a more lethal disease; in their study the proportion of patients who died within 30 days of the diagnosis increased to 13.8% in 2003 from 4.7% in 1991. Many experts believe that the incidence of more severe cases of CDAD represents clonal expansion of more lethal strains. We anticipate that publications addressing this issue will appear in the near future. These authors also found an association between a better outcome and vancomycin as the initial therapy in severe cases. Further studies specifically designed to address this issue are needed.
A final emerging issue with CDAD is the association with classes of antibiotics not previously associated with CDAD. Clindamycin was the classic antibiotic associated with illness due to C. difficile and, in recent years, beta-lactams, particularly advanced generation cephalosporins, and betalactam/beta-lactamase inhibitor combinations have been frequently implicated in CDAD. The common theme among antibiotics associated with CDAD is antimicrobial activity against intestinal anaerobes but no activity against C. difficile. Antibiotics whose antimicrobial spectrum does not include robust activity against gut anaerobes are much less frequently associated with CDAD. Ciprofloxacin was the first fluoroquinolone to gain widespread clinical use. There have been case reports associating ciprofloxacin with CDAD, but clinical experience and published data have not implicated ciprofloxacin as a frequent cause of CDAD. Beginning in the late 1990s, advanced generation quinolones, including levofloxacin, gatifloxacin, and moxyfloxacin, gained widespread use for a variety of infections. Unlike ciprofloxacin, the advanced generation fluoroquinolones have broader activity against anaerobes, and clinical experience and anecdotal reports associating the new quinolones with CDAD have been reported. Several recent papers have demonstrated that fluoroquinolone use was strongly associated with CDAD2. The advanced generation fluoroquinolones are active against anaerobes but lack activity against C. difficile.
Travelers’ diarrhea Between 20% and 50% of individuals traveling to developing countries will develop diarrhea during or shortly after their trip. The risk is highest when traveling to India, Latin America, Africa, the Middle East, and south Asia. The average duration of an episode of travelers’ diarrhea is 3–6 days. About 10% of episodes last longer than 1 week. Basic precautions, such as avoidance of unsafe water and uncooked food, can significantly decrease the risk of diarrhea in travelers. Water or food from street vendors, for instance, is among potential high-risk exposures (Fig. 6.6). An emerging issue with travelers’ diarrhea is the possible association with post-diarrhea irritable bowel syndrome (IBS), which could potentially alter the strategy for preventing and treating travelers’ diarrhea. The most commonly used strategy for short-term visitors to developing countries is to provide an antibiotic for
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Diarrheal disease
Fig. 6.6 Street vendor in a developing country. The basic principle in avoiding travelers’ diarrhea is to drink only water that is bottled or boiled, and eat only cooked food except fruits with intact skin that the traveler peels. Ice, water, or uncooked food from street vendors is a high-risk for enteric pathogens. (Courtesy of Dr R Salata.)
Fig. 6.7 Gram stain of a stool from a patient with Campylobacter, demonstrating curved Gram-negative rods and inflammatory cells. In a stool specimen, Campylobacter has a similar appearance to Vibrio cholera; however, V. cholera does not produce an inflammatory diarrhea and fecal leukocytes are not seen in stool preparations in patients with cholera. (Courtesy of Dr D Bobak.)
‘presumptive therapy’, to be taken if diarrhea develops. Presumptive therapy has been shown to be effective in clinical trials in quickly attenuating and resolving the diarrhea. This strategy has the advantage of limiting antibiotic use to those travelers that develop diarrhea. Travelers’ diarrhea treated with this strategy is thought to be self-limited with no significant long-term consequences. In the past 20 years a number of studies have associated acute bacterial gastroenteritis with the subsequent development of IBS. It is hypothesized that infectious gastroenteritis might cause chronic low-grade inflammation of the gastrointestinal tract leading to IBS. IBS complicating otherwise self-limited travelers’ diarrhea has been reported, but the incidence and prevalence of IBS complicating travelers’ diarrhea are not known. A recent study looked prospectively at the incidence of IBS 6 months after an episode of travelers’ diarrhea3. The authors show that infectious gastroenteritis is a potential risk factor for IBS but fail to demonstrate an association with a specific pathogen. Further studies with longer duration of follow-up are needed to evaluate the natural course of postinfectious IBS. The authors do not want to overstate the potential association between IBS and travelers’ diarrhea, but include it as an emerging issue. The potential for post-travelers’ diarrhea IBS may cause
a re-evaluation of presumptive therapy. The availability of effective new luminal agents may make a preventive strategy more feasible. Rifaximin, a luminal, gastrointestinalselective oral antibiotic, was approved for the treatment of travelers’ diarrhea in 2004. Rifaximin is primarily indicated for enterotoxigenic E. coli (ETEC) in travelers to developing countries (Fig. 6.6). ETEC is the most frequent bacterial cause of travelers’ diarrhea worldwide and especially in Latin America. It usually causes a secretory-type diarrhea through its heat-labile toxin, which structurally resembles the cholera toxin. Diarrhea due to ETEC usually responds to treatment with quinolones, trimethoprim sulfa, and cephalosporins. Rifaximin is an alternative therapy for travelers’ diarrhea due to E. coli (the most common pathogen), but has limited activity against other common pathogens. A recent randomized, double-blind, placebocontrolled trial by DuPont et al. looked at efficacy of rifaximin in preventing travelers’ diarrhea in US students visiting Mexico5. This study showed that rifaximin significantly prevented diarrhea as compared to placebo; it was also found to be well tolerated with minimal effect on enteric flora. More studies are under way to evaluate the role of rifaximin in areas of the world where ETEC is not the most frequent isolate.
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Fig. 6.8 Micrograph of Salmonella, demonstrating flagella, which allow the organism motility. (Courtesy of Dr R Salata.)
Antimicrobial resistance has not become a major issue in ETEC, but is an emerging issue with Salmonella and Campylobacter, the second and third most common bacterial causes of travelers’ diarrhea. Travel is a risk factor for infection with quinolone-resistant Campylobacter. Illness due to Campylobacter usually produces a non-specific inflammatory diarrhea. Wet prep of stools from patients with Campylobacter may reveal bacteria resembling cholera, but can be differentiated from cholera by the presence of fecal leukocytes and a different clinical presentation (Fig. 6.7). Campylobacter is the most common antecedent infection in patients with Guillain–Barré syndrome (GBS); GBS is uncommon in patients with Campylobacter, but almost half of all GBS patients have serologic evidence of recent Campylobacter infection. Salmonella species (Fig. 6.8) are becoming increasingly resistant to quinolones and other antibiotics. Antimicrobial resistance is also an emerging issue with shigellosis; Shigella is a less common cause of travelers’ diarrhea, but may cause severe dysentery. Patients with classic dysentery have tenesmus and frequent small, bloody stools (Fig. 6.9). Shigella infection can also lead to a toxic megacolon, characterized by ileus and marked dilatation of the colon (Figs. 6.10, 6.11).
Fig. 6.9 Wet prep of stool from a patient with shigellosis. Note the presence of fecal leukocytes and red blood cells. Patients with dysentery produce stools with blood and mucus, reflecting marked colonic mucosal inflammation. (Courtesy of Dr R Salata.)
Fig. 6.10 Abdominal plain film showing marked distended colon, in a patient with toxic megacolon due to Shigella. Toxic megacolon can be seen in other conditions, including illness due to Entamoeba histolytica and Clostridium difficile-associated diarrhea. (Courtesy of Dr R Salata.)
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Fig. 6.11 Sigmoidoscopy revealing severe hemorrhagic colitis in a patient infected with shigellosis. Shigella are transmitted from human to human by fecal contamination, with no animal reservoir. In developing countries, most bacterial pathogens that produce gastroenteritis arise from agricultural sources, and shigellosis is uncommon. (Courtesy of Dr R Salata.)
Fig. 6.12 Wet prep of stool in a patient infected with Entamoeba histolytica, demonstrating E. histolytica cysts. The diagnosis of intestinal amebiasis is made by identification of E. histolytica in the stool. (Courtesy of Dr R Salata.)
Figs. 6.13, 6.14 Wet prep of stool in a patient infected with Giardia lamblia. Traditionally, the diagnosis of giardiasis was made by microscopic exam of stools. Recently, antigen tests have been introduced that are used to identify Giardia in stool. These tests are less reliant on the expertise of the individual examining the stool, have increased sensitivity, and can be done quickly. (6.13 courtesy of Dr R Salata; 6.14 courtesy of Dr D Bobak.)
Toxic megacolon can also be seen in infection with Entamoeba histolytica , a protozoan pathogen also seen in travelers, though much less often than bacterial pathogens or Giardia (see below). Infection by E. histolytica occurs by ingestion of mature cysts in fecally contaminated food, water, or hands. Because of the protection conferred by their walls, the cysts can survive days to weeks in the external
environment and are responsible for transmission. In industrialized countries, risk groups include male homosexuals, travelers and recent immigrants, and institutionalized populations. Infection with E. histolytica produces a wide range of clinical presentations, from asymptomatic infection, to invasive intestinal amebiasis (dysentery, colitis, appendicitis, toxic megacolon,
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amebomas), to invasive extraintestinal amebiasis (liver abscess, peritonitis, pleuropulmonary abscess, cutaneous and genital amebic lesions). The diagnosis can be made by examination of a wet prep of stool (Fig. 6.12), but caution must be taken to distinguish E. histolytica from other nonpathogenic protozoa. For asymptomatic infections, iodoquinol, paromomycin, or diloxanide furoate (not commercially available in the US) are the drugs of choice. For symptomatic intestinal disease or extraintestinal infections (e.g. hepatic abscess), the drugs of choice are metronidazole or tinidazole, immediately followed by treatment with iodoquinol, paromomycin, or diloxanide furoate. Nitazoxanide, discussed below, is a new agent recently approved for treating diarrhea due to E. histolytica.
Giardia Giardiasis is an emerging cause of persistent, non-bloody diarrhea in returning travelers. Giardia lamblia is prevalent throughout much of the developing world. Latin America is the most common site of Giardia acquisition, reflecting the relative frequency of American travelers. Homosexual men also have a high prevalence of infection because of specific sexual practices. The diagnosis can be made by a stool
Figs. 6.15, 6.16 Small-bowel biopsies from patients with cryptosporidiosis. Cryptosporidium infects small-bowel enterocytes, but does not cause cell death or invade the mucosa. The result of enterocyte infection is malabsorption of water and solutes, leading to voluminous watery diarrhea, with no inflammatory cells. (Courtesy of Dr R Salata.)
antigen test; examination of a stool may also demonstrate the organism (Figs. 6.13, 6.14). The drug of choice for adults is metronidazole, 500–750 mg three times a day for 7 days. Nitazoxanide (Alinia), approved for use in the United States in 2002, is an emerging new alternative for treating Giardia and Cryptosporidium parvum (500 mg every 12 hours for 3 days).
Cryptosporidium Cryptosporidium is a protozoan parasite that was first described in 1976 but became increasingly important in the 1980s with the advent of the human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) epidemic, and in the last decade has become established as a cause of travelers’ diarrhea8. Cryptosporidium infects humans via ingestion of the robust oocysts shed in the environment from infected animals (human-to-human transmission occurs less often). Cryptosporidiosis is a smallbowel disease, producing a watery, non-inflammatory diarrhea (Figs. 6.15, 6.16). The diagnosis can be made by acid-fast examination of stool (Figs. 6.17, 6.18). This illness causes a self-limited gastroenteritis in immunocompetent hosts. In immunocompromised hosts or
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Figs. 6.17, 6.18 Acid-fast stain of stool revealing Cryptosporidium oocysts. Routine ova and parasite exams will miss Cryptosporidium, and acid-fast staining is usually required to make the diagnosis. Diagnostic tools using antigen tests are becoming available. (6.17 courtesy of Dr R Salata.)
patients receiving immunosuppressive therapy, infection with Cryptosporidium causes profuse and persistent/recurrent diarrhea leading to profound weight loss and wasting. Until recently no treatment was consistently effective as far as parasitological or even clinical response, especially in HIVinfected patients with CD4+
